fig1 illustrates the nucleic acid sequence of a human vldl receptor . fig2 illustrates the nucleic acid sequence of a mouse vldl receptor . fig3 illustrates the amino acid sequence of a human vldl receptor encoded by sequence id no . 1 , utilizing the one letter code as is well known in the art . fig4 illustrates the amino acid sequence of a mouse vldl receptor encoded by sequence id no . 2 , utilizing the one letter code as is well known in the art . the amino acid sequences of the human and mouse vldl receptors have been deduced from their respective cloned cdnas which were isolated and sequenced . see , sequence id nos . 1 and 2 . each protein is predicted to contain 873 amino acid residues , including 27 residues in the signal peptide . thus , the two proteins are identical in size . the cdna nucleotide sequences and predicted amino acid sequences also show high homology between the two species . ( the cdna for the rabbit vldl receptor has been cloned . takahashi et al ., proc . natl . acad . sci . usa , 89 : 9252 - 9256 , ( 1992 )). the n - terminal 27 amino acid sequence ( residues - 27 to - 1 ) is hydrophobic in nature and constitutes the putative signal peptide . the mature human and mouse vldl receptor protein contains three potential n - linked glycosylation sites ( asn - 124 , 737 and 754 ). like the ldl receptor ( yamamoto et al ., cell 39 : 27 - 38 , 1984 ; yamamoto et al ., science 232 : 1230 - 1237 , 1986 ), the human and mouse vldl receptor can be divided into five domains . at the n - terminal region are 8 - fold ˜ 40 residue cysteine - rich repeats that are homologous to the ligand binding region of the ldl receptor which contains 7 - fold repeat units ( esser et al ., j . biol . chem . 263 : 13282 - 13290 , 1988 ; russell et al ., j . biol . chem . 264 : 21682 - 21688 , 1989 ). the next domain , which has homology to the epidermal growth factor precursor , spans 396 amino acids including three cysteine - rich repeats , designated a , b and c . this domain in the ldl receptor is thought to be important for the acid - dependent dissociation of the ligand from the receptor ( davis et al ., nature 326 : 760 - 765 , 1987 ). the next domain , the clustered o - linked sugar region , is well conserved among the known mammalian vldl receptor sequences . the last two domains , the transmembrane domain and the cytoplasmic domain , are completely conserved with no amino acid change between human and mouse vldl receptors . in the ldl receptor , there is a conserved tetrapeptide npxy ( asn - pro - x - tyr ) ( wherein x is any amino acid ) in the cytoplasmic domain which is required for clustering of the ldl receptor in coated pits ( chen et al ., j . biol . chem . 265 : 3116 - 3123 , 1990 ). in the human , mouse and rabbit vldl receptor , the tetrapeptide has the sequence npvy ( asn - pro - val - tyr ). overall , the vldl receptor has evolved at a much slower rate than the ldl receptor . the cloned human vldl receptor cdna probe was used to localize the vldl receptor gene on chromosomal spreads by fluorescence in situ hybridization . a hybridization signal was consistently observed on chromosome band 9p24 . thus , the vldl receptor is on a chromosome different from the ldl receptor which is located on chromosome 19p13 ( lindgren et al ., proc . natl . acad . sci . usa 82 : 8567 - 8571 , 1985 ). the vldl receptor binds to apolipoprotein ( apo ) e - containing lipoproteins , including vldl , intermediate density lipoprotein ( idl ), and β - vldl . it may also bind to chylomicrons and chylomicron remnants which also contain apoe . unlike an ldl receptor , a vldl receptor will not competeably bind to and internalize ldl . as described above , a vldl receptor encompasses any fragment of a vldl receptor which exhibits functional properties of a vldl receptor as defined above . vldl are the precursors of idl and ldl . both idl and ldl have been identified as important risk factors for atherosclerosis . therefore , any therapeutic intervention that lowers idl and ldl will reduce their atherogenic potential . there is recent evidence that lowering serum cholesterol and ldl may actually cause regression of atheromatous lesions . elevated triglycerides are positively correlated with risk for coronary heart disease . much of this association may be related to the fact that high triglycerides often occur in the presence of reduced high density lipoproteins ( hdl ). hdl is thought to be anti - atherogenic and low hdl predisposes one to atherosclerosis . furthermore , high triglycerides are often associated with atherogenic forms of ldl ( e . g ., in familial combined hyperlipidemia and diabetic dyslipidemia ). therapeutic agents that lower plasma vldl will accomplish two important objectives : first , they will lower idl and ldl , the metabolic products of vldl , and total plasma cholesterol , and second , they will also lower triglyceride levels . the lowering of idl and ldl and total plasma cholesterol is highly desirable because of the known strong association between these lipid parameters and coronary heart disease . the lowering of triglyceride is also of benefit especially when it occurs in the presence of atherogenic dyslipidemias , a common situation . in fact , therapeutic intervention in this situation is recommended by the national cholesterol education program ( ncep ) expert panel ( adult treatment panel ii ) ( jama 269 : 3015 - 3023 , 1993 ). it would be useful to control blood levels of β - vldl , vldl and idl through the use of exogenously administered vldl receptor binding to these ligands , thereby decreasing the risk of cardiovascular disease and the resulting need for invasive surgical procedures directed at the heart . currently , there is a clinical protocol approved for the treatment of ldl receptor deficient homozygous fh patients by somatic gene therapy using the human ldl receptor gene ( wilson , hum . gene ther . 3 : 179 - 222 , 1992 ). use of the vldl receptor should also effectively lower ldl in homozygous fh patients because vldl is the precursor of ldl . furthermore , the vldl receptor offers one important advantage over the ldl receptor . fh patients have either no ldl receptor or abnormal ldl receptor . with the expression of the normal ldl receptor , they will develop antibodies to the protein which will eventually interfere with the continued expression of the ldl receptor and the effectiveness of treatment . the vldl receptor , on the other hand , is normally present in multiple tissues in these patients . therefore , the induced over - expression of the vldl receptor in tissues that normally produce it , or the induced expression of the receptor in an ectopic site such as the liver will not cause any untoward immunological response . this is a major advantage of the use of the vldl receptor . the nucleic acid sequence encoding vldl receptor can be administered prophylactically , or to patients having a disease or condition characterized by an elevated plasma lipoprotein level , e . g ., by exogenous delivery of the nucleic acid sequence encoding vldl receptor as naked dna , dna associated with specific carriers , or in a nucleic acid expression vector to a desired tissue by means of an appropriate delivery vehicle , e . g ., a liposome , by use of iontophoresis , electroporation and other pharmacologically approved methods of delivery . routes of administration may include intramuscular , intravenous , aerosol , oral ( tablet or pill form ), topical , systemic , ocular , as a suppository , intraperitoneal and / or intrathecal . the specific delivery route of a vldl receptor will depend on the use of the vldl receptor . c . localization to nuclear compartment utilizing nuclear targeting site found on most nuclear proteins , d . transfection of cells ex vivo with subsequent reimplantation or administration of the transfected cells , at least three types of delivery strategies are useful in the present invention , including : injection of naked vldl receptor dna or charge modified naked vldl receptor dna , particle carrier drug delivery vehicles which are also suitable for delivery of vldl receptor proteins , and retroviral expression vectors . unmodified nucleic acid sequence encoding vldl receptors , like most small molecules , are taken up by cells , albeit slowly . to enhance cellular uptake , the nucleic acid sequence encoding vldl receptor may be modified in ways which reduce its charge but will maintain the expression of specific functional groups in the final translation product . this results in a molecule which is able to diffuse across the cell membrane , thus removing the permeability barrier . chemical modifications of the phosphate backbone will reduce the negative charge allowing free diffusion across the membrane . this principle has been successfully demonstrated for antisense dna technology which shows that this is a feasible approach . in the body , maintenance of an external concentration will be necessary to drive the diffusion of the modified nucleic acid sequence encoding the vldl receptor into the cells of the tissue . administration routes which allow the tissue to be exposed to a transient high concentration of the nucleic acid sequence encoding the vldl receptor , which is slowly dissipated by systemic adsorption are preferred . intravenous administration with a drug carrier designed to increase the circulation half - life of the nucleic acid sequence encoding the vldl receptor or vldl receptor proteins can be used . the size and composition of the drug carrier restricts rapid clearance from the blood stream . the carrier , made to accumulate at the desired site of transfer , can protect the nucleic acid sequence encoding the vldl receptor from degradative processes . drug delivery vehicles are effective for both systemic and topical administration . they can be designed to serve as a slow release reservoir , or to deliver their contents directly to the target cell . an advantage of using direct delivery drug vehicles is that multiple molecules are delivered per uptake . such vehicles have been shown to increase the circulation half - life of drugs which would otherwise be rapidly cleared from the blood stream . some examples of such specialized drug delivery vehicles which fall into this category are liposomes , hydrogels , cyclodextrins , biodegradable nanocapsules , and bioadhesive microspheres . from this category of delivery systems , liposomes are preferred . liposomes increase intracellular stability , increase uptake efficiency and improve biological activity . liposomes are hollow spherical vesicles composed of lipids arranged in a similar fashion as those lipids which make up the cell membrane . they have an internal aqueous space for entrapping water soluble compounds and range in size from 0 . 05 to several microns in diameter . several studies have shown that liposomes can deliver nucleic acids to cells and that the nucleic acid remains biologically active . for example , a liposome delivery vehicle originally designed as a research tool , lipofectin , has been shown to deliver intact mrna molecules to cells yielding production of the corresponding protein . liposomes offer several advantages : they are non - toxic and biodegradable in composition ; they display long circulation half - lives ; and recognition molecules can be readily attached to their surface for targeting to tissues . finally , cost effective manufacture of liposome - based pharmaceuticals , either in a liquid suspension or lyophilized product , has demonstrated the viability of this technology as an acceptable drug delivery system . other controlled release drug delivery systems , such as nanoparticles and hydrogels may be potential delivery vehicles for a nucleic acid sequence encoding a vldl receptor . these carriers have been developed for chemotherapeutic agents and protein - based pharmaceuticals ( such as vldl receptor proteins ), and consequently , can be adapted for nucleic acid delivery . chemical modification of the nucleic acid sequence encoding a vldl receptor to neutralize negative charge may be all that is required for penetration . however , in the event that charge neutralization is insufficient , the nucleic acid sequence encoding a vldl receptor can be co - formulated with permeability enhancers , such as azone or oleic acid , in a liposome . the liposomes can either represent a slow release presentation vehicle in which the modified nucleic acid sequence encoding a vldl receptor and permeability enhancer transfer from the liposome into the targeted cell , or the liposome phospholipids can participate directly with the modified nucleic acid sequence encoding a vldl receptor and permeability enhancer can participate directly with the modified nucleic acid encoding a vldl receptor and permeability enhancer facilitating cellular delivery . in some cases , both the nucleic acid encoding a vldl receptor and permeability enhancer can be formulated into a suppository formulation for slow release . the nucleic acid sequence encoding a vldl receptor or a vldl receptor protein may also be systemically administered . systemic absorption refers to the accumulation of drugs in the blood stream followed by distribution throughout the entire body . administration routes which lead to systemic absorption include : intravenous , intramuscular , subcutaneous , intraperitoneal , intranasal , intrathecal and ophthalmic . a gene gun may also be utilized . administration of dna - coated microprojectiles by a gene gun requires instrumentation but is as simple as direct injection of dna . a construct bearing the gene of interest is precipitated onto the surface of microscopic metal beads . the microprojectiles are accelerated with a shock wave or expanding helium gas , and penetrate tissues to a depth of several cell layers . this approach permits the delivery of foreign genes to the skin of anesthetized animals . this method of administration achieves expression of transgenes at high levels for several days and at detectable levels for several weeks . each of these administration routes exposes the nucleic acid sequence encoding a vldl receptor to an accessible targeted tissue . subcutaneous administration drains into a localized lymph node which proceeds through the lymphatic network into the circulation . the rate of entry into the circulation has been shown to be a function of molecular weight or size . the use of a liposome or other drug carrier localizes the nucleic acid sequence encoding vldl receptor at the lymph node . the nucleic acid sequence encoding vldl receptor can be modified to diffuse into the cell , or the liposome can directly participate in the delivery of either the unmodified or modified nucleic acid sequence encoding vldl receptor to the cell . liposomes injected intravenously show accumulation in the liver , lung and spleen . the composition and size can be adjusted so that this accumulation represents 30 % to 40 % of the injected dose . the remaining dose circulates in the blood stream for up to 24 hours . the chosen method of delivery should result in cytoplasmic accumulation and molecules should have some nuclease - resistance for optimal dosing . nuclear delivery may also be used . most preferred delivery methods include liposomes ( 10 - 400 nm ), hydrogels , controlled - release polymers , microinjection or electroporation ( for ex vivo treatments ) and other pharmaceutically applicable vehicles . the dosage will depend upon the disease indication and the route of administration but should be between 1 - 1000 μg / kg of body weight / day . the duration of treatment will extend through the course of the disease symptoms , possibly continuously . the number of doses will depend upon disease delivery vehicle and efficacy data from clinical trials . another method of administration involves the use of a dna transporter system for inserting specific dna into a cell . the dna transporter system comprises a plurality of a first dna binding complex , said complex including a first binding molecule capable of non - covalently binding to dna , said first binding molecule covalently linked to a surface ligand , said surface ligand capable of binding to a cell surface receptor ; a plurality of a second dna binding complex , said complex including a second binding molecule capable of non - covalently binding to dna , said second binding molecule covalently linked to a nuclear ligand , said nuclear ligand capable of recognizing and transporting a transporter system through a nuclear membrane ; wherein said plurality of first and second dna binding complexes are capable of simultaneously , non - covalently binding to a specific dna . additionally , a plurality of a third dna binding complex may be used , said complex includes a third binding molecule capable of non - covalently binding to dna , said third binding molecule covalently linked to a virus ; wherein said plurality of third dna binding complexes are capable of simultaneously , non - covalently binding to a specific dna . the first binding molecule , the second binding molecule and third binding molecule can each be selected from the group consisting of spermine , spermine derivative , histones , cationic peptides and polylysine . spermine derivative refers to analogues and derivatives of spermine and include compounds as set forth in international publication no . wo 93 / 18759 , filed mar . 19 , 1993 and published sep . 30 , 1993 hereby incorporated by reference . establishment of therapeutic levels of nucleic acid sequence encoding vldl receptor within the cell is dependent upon the rates of uptake and degradation . decreasing the degree of degradation will prolong the intracellular half - life of the vldl receptor gene . descriptions of useful systems are provided in the art cited above , all of which is hereby incorporated by reference . a vldl receptor nucleic acid sequence may be administered utilizing an ex vivo approach whereby cells are removed from an animal , transduced with the vldl receptor nucleic acid sequence and reimplanted into the animal . the liver can be accessed by an ex vivo approach by removing hepatocytes from an animal , transducing the hepatocytes in vitro with the vldl receptor nucleic acid sequence and reimplanting them into the animal ( e . g ., as described for rabbits by chowdhury et al , science 254 : 1802 - 1805 , 1991 , or in humans by wilson , hum . gene ther . 3 : 179 - 222 , 1992 ) incorporated herein by reference . the vldl receptor nucleic acid sequence may be administered utilizing an in vivo approach whereby the gene will be administered directly to an animal by intravenous injection , intramuscular injection , or by catheterization and direct delivery of the gene via the blood vessels supplying the target organ . since the vldl receptor is normally expressed in multiple tissues and organs including heart , skeletal muscle , adipose tissues , spleen , lung , brain , kidney , testis , adrenal , small intestine , and other tissues , any of these tissues can be target organs . among these tissues , skeletal muscle is one tissue that is readily accessible by intramuscular injection or intravenous injection . expression will be achieved using a skeletal muscle - specific promoter for the nucleic acid sequence encoding vldl receptor . normally there is little expression of the vldl receptor in the liver . this organ is , however , also a good target organ for expression because the liver clears large volumes of blood and is able to metabolize the apoe - containing lipoproteins that bind to the vldl receptor and become internalized in this organ . the liver can also be accessed by an in vivo approach by administration of the nucleic acid sequence encoding vldl receptor intravenously , intraportally ( via the portal vein ) or intra - arterially into the hepatic artery . many nonviral techniques for the delivery of a vldl receptor nucleic acid sequence into a cell can be used , including direct naked dna uptake ( e . g ., wolff et al ., science 247 : 1465 - 1468 , 1990 ), receptor - mediated dna uptake , e . g ., using dna coupled to asialoorosomucoid which is taken up by the asialoglycoprotein receptor in the liver ( wu and wu , j . biol . chem . 262 : 4429 - 4432 , 1987 ; wu et al ., j . biol . chem . 266 : 14338 - 14342 , 1991 ), and liposome - mediated delivery ( e . g ., kaneda et al ., expt . cell res . 173 : 56 - 69 , 1987 ; kaneda et al ., science 243 : 375 - 378 , 1989 ; zhu et al ., science 261 : 209 - 211 , 1993 ). many of these physical methods can be combined with one another and with viral techniques ; enhancement of receptor - mediated dna uptake can be effected , for example , by combining its use with adenovirus ( curiel et al ., proc . natl . acad . sci . usa 88 : 8850 - 8854 , 1991 ; cristiano et al ., proc . natl . acad . sci . usa 90 : 2122 - 2126 , 1993 ). the construction of expression vectors encoding a vldl nucleic acid sequence encoding a vldl receptor in whole or in part or in modified form will be performed utilizing standard techniques known to those of ordinary skill in the art as set forth in , for example , maniatis , fritsch and sambrook , molecular cloning : a laboratory manual . cold spring harbor laboratory , cold spring harbor , n . y ., 1982 . the nucleic acid sequence encoding a vldl receptor or a functional part thereof will be inserted at one end of a promoter , typically but not necessarily the 3 &# 39 ; end , the promoter capable of directing appropriate transcription of the vldl nucleic acid sequence . the promoter used can be any that gives good expression of a vldl receptor , these include the retroviral long terminal repeat ( ltr ) promoter , rsv - ltr , muv - ltr , promoters from cytomegalovirus , apolipoprotein a - i , albumin ( together with its enhancer ), transthyretin , transferrin , skeletal muscle actin , metallothionein , or a myogenic specific promoter selected from a group consisting of skeletal alpha actin gene promoter , first myosin light chain 1 promoter , myosin heavy chain promoter , tropinin t promoter , muscle creatinine kinase promoter / enhancer , cytomegalovirus promoter , rsv promoter and rous sarcoma virus ltr . in the preferred embodiment the skeletal alpha actin promoter is used . other promoters as are known in the art may also be used . also , specific embodiments may include the addition of regulatory promoter elements to regulate the expression of any specific nucleic acid sequence in myogenic tissue . in the preferred embodiment , vitamin d is used to regulate expression . one skilled in the art will recognize that the selection of the promoter will depend on the vector , the vldl receptor nucleic acid sequence utilized and the desired biological effect . one skilled in the art will also recognize that in the selection of a promoter the parameters can include : achieving sufficiently high levels of gene expression to achieve a physiological effect ; maintaining a critical steady state of gene expression ; achieving temporal regulation of gene expression ; achieving tissue - specific expression ; achieving pharmacological , endocrine , paracrine or autocrine regulation of gene expression ; and preventing inappropriate or undesirable levels of expression . any given set of selection requirements will depend on the conditions , but can be readily determined once the specific requirements are determined . genomic sequences comprising an intron or introns and in certain embodiments including regulatory sequences for transcription or rna stability may be included . these may include 3 &# 39 ; untranslated sequences possibly including regulatory sequences for rna stability . a polyadenylation signal from genes such as growth hormone or sv40 or others as are known in the art will be ligated to one end of the nucleic acid sequence , typically the 3 &# 39 ; end of the nucleic acid sequence . in the case of a retroviral vector the elements include two long terminal repeat sequences , the y ( packaging ) sequence which may extend into the gag region of the retrovirus and may be modified to eliminate splice signals or translation initiation sites , a promotor capable of producing appropriately regulated transcription of vldl receptor nucleic acid sequences , in alternate embodiments the retroviral vector can include a selectable marker for chemical , pharmacological , or fluorescent elimination of non - transduced cells and / or other retroviral sequences required for integrity and function of the retroviral vector . a number of viral vectors can be used to deliver a vldl receptor nucleic acid sequence , including papovaviruses , adenovirus , vaccinia virus , adeno - associated virus , herpesviruses , retroviruses of avian , murine , and human origin and other viruses as are known in the art ( reviewed by morgan and anderson , ann . rev . biochem . 62 : 191 - 217 , 1993 incorporated herein by reference .) retroviral vectors can be used for transducing the vldl receptor vector into liver cells or muscle . the advantage of retrovirus as a delivery system is the ability of the virus to integrate into the host cell chromosomes ( reviewed by a . d . miller , hum . gene ther . 1 : 5 - 14 , 1990 ). the vldl receptor vector can be delivered by retroviral - mediated gene transfer , a two - component system consisting of the packaging cell and the viral vector . the vldl receptor nucleic acid sequence can be inserted into the retroviral vector by molecular cloning ( e . g ., as described by wilson , hum . gene ther . 3 : 179 - 222 , 1992 ). the virus particle assembled by the producer cell line ( i . e ., a packaging cell line containing the vldl receptor - containing retroviral vector ) will be used to transfer the vldl receptor nucleic acid sequence to a target organ or tissue such as liver cells in vivo ( following partial hepatectomy because only dividing cells take up retroviral vectors ), isolated hepatocytes in vitro or skeletal muscle in viva . the virus particle will bind to the cell and deliver the vldl receptor nucleic acid sequence which is integrated into the host genome and result in stable long - term expression of the vldl receptor . two major limitations to the use of retroviral vectors are the restricted host - cell range and the inability to obtain high - titer virus . these limitations have been overcome by burns et al ., proc . natl . acad . sci . usa 90 : 8033 - 8037 , 1993 . they replaced the retroviral envelope glycoprotein with the g glycoprotein of vesicular stomatitis virus . such vectors can be produced in high titer (& gt ; 10 9 colony - forming units / ml ) and can infect diverse cell types . partial hepatectomy may not be necessary for liver expression using such vectors . the nucleic acid sequence encoding vldl receptor can be delivered by using this or a similarly designed vector in vivo by intravenous administration . the other viral vector delivery system that will be used is the adenovirus system . the vldl receptor nucleic acid sequence can be used to replace the el region of the adenovirus using the method described by graham and prevec ( methods molec . biol ., vol . 7 , e . j . murray , ed ., humana press , n . j ., pp . 109 - 128 , 1991 ) using recombination in 293 cells incorporated herein by reference . the replication - defective vldl receptor nucleic acid sequence / adenovirus can be injected intravenously , intramuscularly , intraportally or intra - arterially ( hepatic artery ). to date , adenovirus - mediated expression vectors generally direct the transient expression of the therapeutic gene . improvements and refinements in vector structure and design may lead to diminished immunogenicity and allow the vector to be administered repeatedly . other modifications may result in the ability of the vldl receptor nucleic acid sequence to be integrated in the host chromosomes allowing for stable expression . other viral vector delivery systems as are known in the art will also be used for the targeted transfer of the vldl receptor nucleic acid sequence . the following examples are offered by way of illustration and are not intended to limit the invention in any manner . methods of augmenting levels of expression of human or mouse vldl receptor vector normally , the vldl receptor is expressed at a high level in skeletal muscle , although the exact level of expression has not been defined . for a therapeutic effect using muscle expression , it will be necessary to increase vldl expression by about 5 % or more . the persistent over - expression of the vldl receptor in muscle by this amount should lead to a substantial lowering of plasma vldl , idl and ldl . liver normally does not express detectable amounts of vldl receptor . therefore , the induced expression of low level of vldl receptor should have a substantial effect on plasma lipoproteins . the minimal level aimed at is an average expression of one molecule per cell ( i . e ., 1000 receptors per cell if 0 . 1 % of hepatocytes show expression , 100 receptors per cell if 1 % express it and so on ). for patients with more severe elevation of ldl cholesterol , e . g ., levels of about 200 mg / dl to 250 mg / dl or higher , a higher level of expression will be targeted , e . g ., aiming at 10 - 1000 molecules per cell . the relatively high level of expression will be a function of the nucleic acid sequence encoding vldl receptor construct ( e . g ., different promoters will have different activities ) and the delivery method ( e . g ., naked dna delivery , liposome delivery , receptor - mediated delivery , retrovirus - mediated delivery and adenovirus - mediated delivery will have different efficiencies , and in vivo versus ex vivo delivery will also produce different results ) which can be experimented on and optimized . the level of expression will be determined at the rna level by rna blotting or s1 protection assay , and at the protein level by immunoblot analysis and by receptor - binding assay by the method of goldstein et al ., methods enzymol . 98 : 241 - 260 , 1983 . methods of enhancing vldl receptor activity by expression of lipoprotein lipase ( lpl ) vldl receptor and lpl are expressed in similar tissues , e . g ., heart , skeletal muscle and adipose tissue . lpl has been found to play an important role in the receptor - mediated uptake of various lipoproteins ( eisenberg et al ., j . clin . invest . 90 : 2013 - 2021 ) via ldl receptor related protein (&# 34 ; lrp &# 34 ;) ( chappell et al ., j . biol . chem . 267 : 25764 - 25767 , 1992 ; beisiegel et al ., proc . natl . acad . sci . usa 88 : 8342 - 8346 , 1991 ), and ldl receptor ( mulder et al ., j . biol . chem . 268 : 9369 - 9375 , 1993 ). it also may be involved in the non - receptor mediated uptake of lipoproteins ( mulder et al ., j . biol . chem . 268 : 9369 - 9375 , 1993 ; rumsey et al ., j . clin . invest . 90 : 1504 - 1512 , 1992 ; williams et al ., j . biol . chem . 267 : 13284 - 13292 , 1992 ). the co - expression of lpl in the same tissues that express the vldl receptor will enhance the activity of the latter . to accomplish this , an lpl gene vector will be delivered using a similar design as the vldl gene vector . the two vectors can be delivered simultaneously , or they can be delivered consecutively with a varying period in between . it is expected that the activity of the vldl receptor will be markedly enhanced by this method of co - expression . the human or mouse vldl receptor may be used without modification for gene therapy . however , variants of the human or mouse nucleic acid sequence encoding vldl receptor generated by site - specific mutagenesis and having the following properties , such as ; increased affinity for the ligand , recognition of apob - containing lipoproteins in addition to apoe - containing lipoproteins , or usefulness for screening for pharmaceutical agents that bind to the vldl receptor and modulate its activity ( see , example 5 below ) will also be useful . selection from a wide variety of methods for site - directed mutagenesis for modifying the vldl receptor , including the methods of taylor et al ., nucleic acids res . 13 : 8765 - 8785 , 1985 , and of deng and nickoloff , anal . biochem . 200 : 81 - 88 , 1992 , incorporated herein by reference , may be used . determination of serum chemistry values for patients undergoing vldl gene therapy a large number of serum chemistry values will be obtained as for all patients with hyperlipidemia who are at risk for accelerated atherosclerosis . the following values are specifically measured with respect to vldl receptor gene therapy : total serum cholesterol , triglyceride , ldl - cholesterol , hdl , apoa - i , apoe ( level and isoform ), apob , and lipoprotein ( a ). the aim of vldl gene therapy is to reduce total serum cholesterol ( and triglyceride if it is elevated ), ldl - cholesterol and both apoe and apob . the effect of treatment on hdl and its major apolipoprotein , apoa - i , will be monitored . lipoprotein ( a ) level is relatively resistant to various forms of medication . since vldl receptor gene therapy will lower the apob - containing lipoproteins ( vldl , idl and ldl ), it is likely that the level of lipoprotein ( a ), which contains apob - 100 as an essential component , will also be lowered . screening for compounds having a pharmacological effect on human or mouse vldl receptor the highest level of expression of the vldl receptor is found in the heart . the heart also synthesizes lipoprotein lipase ( lpl ) at a high level . vldl receptor and lpl , acting separately or in concert , mediate the uptake of lipids ( vldl and fatty acids ) from the circulation . these lipids constitute a major source of energy for the heart . disruption of vldl receptor function will likely lead to cardiac dysfunction , such as congestive heart failure , cardiomyopathy or arrhythmia . by using wild - type human or mouse or variant human or mouse vldl receptors expressed in vitro , we can screen for various natural and synthetic compounds that bind to the vldl receptor ( by a modification of the method of goldstein et al ., methods enzymol . 98 : 241 - 260 , 1983 , using apoe - containing lipoproteins instead of ldl as a competing ligand ). compounds identified by in vitro binding experiments can be tested for metabolic effects in vitro , e . g ., do they block or modulate vldl uptake , or lpl action ? do they modulate hmgcoa reductase activity ( by the method of goldstein et al ., methods enzymol . 98 : 241 - 260 , 1983 )? the bioactive compounds can be tested in experimental animals in vivo . the compounds found to have beneficial therapeutic effects in congestive heart failure , cardiomyopathy or cardiac arrhythmia may ultimately be used as therapeutic agents in humans or animals . the high concentration of vldl receptor in heart may provide a useful handle for developing in vivo diagnostic imaging equipment . natural or synthetic ligands for this receptor can be labeled ( e . g ., with 125 i or other radionuclides ) and injected intravenously . the imaging and quantitation of the radionuclide uptake by the heart will allow the structure and function of the heart to be studied in vivo . the ligands in such studies include vldl , apoe - containing vesicles , labeled monoclonal antibodies against the vldl receptor , or other natural or synthetic compounds identified by in vitro binding assays . labels which are detectable by magnetic resonance imaging , positron emission tomography or computerized axial tomography are also suitable . the mouse is a useful animal for both genetic and conventional therapy . it is especially useful for drug screening . the vldl receptor nucleic acid sequence will be useful in this type of screening . since the mouse vldl receptor sequence is highly homologous to the human vldl receptor , sharing over 95 % sequence identity with the latter , many of the methods applicable to the mouse will be applicable to humans . all the uses of the human vldl receptor discussed in the previous sections can be applied to the mouse vldl receptor as well . in addition , natural or synthetic compounds that bind to the vldl receptor , or that modulate vldl receptor expression can be studied in mouse in vivo before they are used for clinical trials in humans . the human or mouse vldl nucleic acid sequences or vectors containing such sequences can be used as probes , as is known in the art , in order to screen cdna or genomic libraries and isolate additional vldl receptors and / or other as yet unidentified lipoprotein receptors . the human or mouse vldl nucleic acid sequences or vectors containing such sequences can also be utilized to perform in situ hybridizations , as is known in the art , in order to further characterize the tissue distribution of the vldl receptor or homologous lipoprotein receptors in various species . stably transformed or transfected cell lines which express vldl receptors are useful for the screening of compounds which will specifically bind to these vldl receptors . nucleic acid sequences encoding vldl receptor genes may be isolated and cloned as is known in the art , as set forth in , for example , maniatis , fritsch and sambrook , molecular cloning : a laboratory manual . cold spring harbor laboratory , cold spring harbor , n . y ., 1982 . probes generated from ldl receptor nucleic acid sequences or vldl receptor nucleic acid sequences as are known including rabbit , mouse and human may be used . for example , the human and mouse vldl receptor genes were isolated utilizing probes based on the rabbit vldl receptor sequence . it will be readily apparent to one skilled in the art that various substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention . __________________________________________________________________________sequence listing ( 1 ) general information :( iii ) number of sequences : 4 ( 2 ) information for seq id no : 1 :( i ) sequence characteristics :( a ) length : 3330 base pairs ( b ) type : nucleic acid ( c ) strandedness : single ( d ) topology : linear ( xi ) sequence description : seq id no : 1 : tttcccctccccgcccccaccttcttcctcctttcggaagggctggtaacttgtcgtgcg60gagcgaacggcggcggcggcggcggcggcggcggcaccatccaggcgggcaccatgggca120cgtccgcgctctgggcgctctggctgctcgtcgcgctgtgctgggcgccccgggagagcg180gcgccaccggaaccgggagaaaagccaaatgtgaaccctcccaattccagtgcacaaatg240gtcgctgtattacgctgttgtggaaatgtgatggggatgaagactgtgttgacggcagtg300atgaaaagaactgtgtaaagaagacgtgtgctgaatctgacttcgtgtgcaacaatggcc360agtgtgttcccagccgatggaagtgtgatggagatcctgactgcgaagatggttcagatg420aaagcccagaacagtgccatatgagaacatgccgcatacatgaaatcagctgtggcgccc480attctactcagtgtatcccagtgtcctggagatgtgatggtgaaaatgattgtgacagtg540gagaagatgaagaaaactgtggcaatataacatgtagtcccgacgagttcacctgctcca600gtggccgctgcatctccaggaactttgtatgcaatggccaggatgactgcagcgatggca660gtgatgagctggactgtgccccgccaacctgtggcgcccatgagttccagtgcagcacct720cctcctgcatccccatcagctgggtatgcgacgatgatgcagactgctccgaccaatctg780atgagtccctggagcagtgtggccgtcagccagtcatacacaccaagtgtccagccagcg840aaatccagtgcggctctggcgagtgcatccataagaagtggcgatgtgatggggaccctg900actgcaaggatggcagtgatgaggtcaactgtccctctcgaacttgccgacctgaccaat960ttgaatgtgaggatggcagctgcatccatggcagcaggcagtgtaatggtatccgagact1020gtgtcgatggttccgatgaagtcaactgcaaaaatgtcaatcagtgcttgggccctggaa1080aattcaagtgcagaagtggagaatgcatagatatcagcaaagtatgtaaccaggagcagg1140actgcagggactggagtgatgagcccctgaaagagtgtcatataaacgaatgcttggtaa1200ataatggtggatgttctcatatctgcaaagacctagttataggctacgagtgtgactgtg1260cagctgggtttgaactgatagataggaaaacctgtggagatattgatgaatgccaaaatc1320caggaatctgcagtcaaatttgtatcaacttaaaaggcggttacaagtgtgaatgtagtc1380gtggctatcaaatggatcttgctactggcgtgtgcaaggcagtaggcaaagagccaagtc1440tgatcttcactaatcgaagagacatcaggaagattggcttagagaggaaagaatatatcc1500aactagttgaacagctaagaaacactgtggctctcgatgctgacattgctgcccagaaac1560tattctgggccgatctaagccaaaaggctatcttcagtgcctcaattgatgacaaggttg1620gtagacatgttaaaatgatcgacaatgtctataatcctgcagccattgctgttgattggg1680tgtacaagaccatctactggactgatgcggcttctaagactatttcagtagctaccctag1740atggaaccaagaggaagttcctgtttaactctgacttgcgagagcctgcctccatagctg1800tggacccactgtctggctttgtttactggtcagactggggtgaaccagctaaaatagaaa1860aagcaggaatgaatggattcgatagacgtccactggtgacagcggatatccagtggccta1920acggaattacacttgaccttataaaaagtcgcctctattggcttgattctaagttgcaca1980tgttatccagcgtggacttgaatggccaagatcgtaggatagtactaaagtctctggagt2040tcctagctcatcctcttgcactaacaatatttgaggatcgtgtctactggatagatgggg2100aaaatgaagcagtctatggtgccaataaattcactggatcagagctagccactctagtca2160acaacctgaatgatgcccaagacatcattgtctatcatgaacttgtacagccatcaggta2220aaaattggtgtgaagaagacatggagaatggaggatgtgaatacctatgcctgccagcac2280cacagattaatgatcactctccaaaatatacctgttcctgtcccagtgggtacaatgtag2340aggaaaatggccgagactgtcaaagtactgcaactactgtgacttacagtgagacaaaag2400atacgaactcaacagaaatttcagcaactagtggactagttcctggagggatcaatgtga2460ccacagcagtatcagaggtcagtgttcccccaaaagggacttctgccgcatgggccattc2520ttcctctcttgctcttagtgatggcagcagtaggtggctacttgatgtggcggaattggc2580aacacaagaacatgaaaagcatgaactttgacaatcctgtgtacttgaaaaccactgaag2640aggacctctccatagacattggtagacacagtgcttctgttggacacacgtacccagcaa2700tatcagttgtaagcacagatgatgatctagcttgacttctgtgacaaatgttgacctttg2760aggtctaaacaaataatacccccgtcggaatggtaaccgagccagcagctgaagtctctt2820tttcttcctctcggctggaagaacatcaagatacctttgcgtggatcaagcttgtgtact2880tgaccgtttttatattacttttgtaaatattcttgtccacattctacttcagctttggat2940gtggttaccgagtatctgtaacccttgaatttctagacagtattgccacctctggccaaa3000tatgcactttccctagaaagccatattccagcagtgaaacttgtgctatagtgtatacca3060cctgtacatacattgtataggccatctgtaaatatcccagagaacaatcactattcttaa3120gcactttgaaaatatttctatgtaaattattgtaaactttttcaatggttgggacaatgg3180caataggacaaaacgggttactaagatgaaattgccaaaaaaatttataaactaattttg3240tacgtatgaatgatatctttgacctcaatggaggtttgcaaagactgagtgttcaaacta3300ctgtacattttttttcaagtgctaaaaaat3330 ( 2 ) information for seq id no : 2 :( i ) sequence characteristics :( a ) length : 3116 base pairs ( b ) type : nucleic acid ( c ) strandedness : single ( d ) topology : linear ( xi ) sequence description : seq id no : 2 : caccatccgggcgggcagcatgggcacgtccgcgcgctgggccctgtggctgctgctcgc60gctgtgctgggcgccccgggacagcggcgccactgcaagcgggaagaaagccaaatgtga120tagctcccagtttcagtgcacaaatggccgctgcattaccctgctgtggaaatgtgatgg180agatgaagactgtgcggatggcagcgacgagaagaactgtgtaaagaagacgtgtgctga240gtctgacttcgtgtgcaaaaacggccagtgtgttcctaacagatggcagtgtgacgggga300tcctgattgcgaaaacggttctgatgaaagccctgaacagtgccatatgagaacatgccg360cataaatgaaatcagctgtggcgcccgttctactcagtgtatccccgtctcctggagatg420cgatggtgaaaatgattgtgacaatggagaagatgaagaaaactgtggcaacataacatg480tagtgcagatgagttcacttgctccagtggccgctgcgtctccagaaactttgtgtgcaa540tggccaggatgactgtgacgatggcagtgatgagctggactgtgctccaccaacctgcgg600agcccacgagttccagtgcagcacctcttcctgcattcccctcagctgggtgtgtgatga660tgacgcagactgttcagaccaatcagacgagtctcttgagcagtgtggccgtcagcctgt720gatacataccaaatgtcctaccagtgagatccagtgtggctctggcgagtgcattcacaa780aaaatggcggtgtgacggagaccctgactgcaaggacggcagcgatgaggtcaactgccc840ttctcgaacctgccgacctgaccagtttgaatgtgaagatggtagctgtatccacggcag900caggcaatgcaatggcatccgagactgtgttgatggctctgatgaagtcaactgcaaaaa960cgtcaatcagtgcctgggccctggaaagttcaagtgcagaagcggggaatgcatagacat1020gagcaaagtatgtgaccaggaacaagactgcagagactggagtgacgagcccctgaagga1080atgccatatcaacgaatgcctggtcaataatggtggctgttcccatatctgcaaagacct1140agttataggttatgagtgtgattgtgcagctgggtttgaactgatagataggaaaacctg1200tggagatattgatgaatgccaaaacccggggatctgcagtcaaatttgtatcaacttaaa1260aggcggttacaagtgtgaatgtagtcgtggctatcaaatggatcttgccactggcgtgtg1320caaggcagtaggcaaagagccgagtctgatcttcactaatcgaagagacatcaggaagat1380tggcctagagagaaaggaatacatccaacttgtagagcaactaaggaacacggtggctct1440cgatgcggacattgcagctcagaagctgttttgggctgatctcagccagaaggccatctt1500cagtgcctcaattgatgacaaggttggtagacattttaaaatgatcgacaatgtctataa1560tcctgcagccattgctgttgattgggtgtacaagaccatctactggactgatgcggcttc1620taagactatttcagtagctaccctagacggagccaagaggaagttcctgtttaattctga1680cttgcgagagcctgcctccatagctgtggatccgttgtcgggctttgtttactggtcaga1740ctggggcgagccagctaaaatagaaaaagcaggaatgaatggatttgatagacgtcctct1800ggtgacggaggacatccaatggcctaatggaattacactcgaccttgtcaaaagccgcct1860ctactggctggattccaagttgcacatgctctctagtgtggacctgaatggtcaagatcg1920taggatagtgctcaagtctctggagttcctagctcatcctcttgcactcaccatatttga1980ggatcgcgtctactggatagatggagaaaatgaagcagtgtacggtgccaataaattcac2040tgggtcagagctggccactctagtgaattccctcaatgatgcccaagacatcattgtcta2100ccatgaactcgtccagccgtcaggtaaaaactggtgtgaagacgatatggagaatggagg2160atgtgaatatctctgcctgccagcaccacagatcaatgaccactctccaaaatatacctg2220ttcctgtcccaatgggtacaatctcgaagaaaatggacgagagtgtcaaagtacttcaac2280tcctgtgacttacagtgagacaaaagatatcaacacaacagacattctacgaactagtgg2340actggttcctggagggatcaatgtgaccacagcagtatcagaagtcagtgttcccccaaa2400agggacttcagctgcctgggccatccttcctctcttgctcttagtgatggcagcagtagg2460tggctacttgatgtggaggaattggcaacataaaaacatgaaaagcatgaactttgacaa2520tcctgtgtacttgaagaccactgaagaggacctgtcgatagacattggtagacacagcgc2580ttctgtaggacacacatacccagcaatatcagttgtaagcacagatgatgatctggcttg2640agttctgaacaaatcttggtctatgaggtctacaccaataacaccctactctggaatggt2700aacagagccagcgctgaagtctcctttcttcctcccatctggaagaacatcaagatatct2760ttttgtggatcaagtttgagtacttgatcatttttatattacttttgtaaatattcttgg2820ccacattctacttcagctctggatgtggttaccaagtatctgtaacccttgagcccctag2880acagtattgccatctctggccaaatatgcactttccctagaaagccatattccagcaatg2940aacgttgtgctatagtgactcccacctgtacatacattgtataggccacctgtacatatc3000ccagagaacaatcactattcttaagcactttgaagatatttctatgtaaattattgtaaa3060ctttttcaatggttgggacaatggcaataggataaaacgggttactaagatgaaat3116 ( 2 ) information for seq id no : 3 :( i ) sequence characteristics :( a ) length : 846 amino acids ( b ) type : amino acid ( c ) strandedness : single ( d ) topology : linear ( xi ) sequence description : seq id no : 3 : glyarglysalalyscysgluproserglnpheglncysthrasngly151015argcysilethrleuleutrplyscysaspglyaspgluaspcysval202530aspglyseraspglulysasncysvallyslysthrcysalagluser354045aspphevalcysasnasnglyglncysvalproserargtrplyscys505560aspglyaspproaspcysgluaspglyseraspgluserproglugln65707580cyshismetargthrcysargilehisgluilesercysglyalahis859095serthrglncysileprovalsertrpargcysaspglygluasnasp100105110cysaspserglygluaspglugluasncysglyasnilethrcysser115120125proaspgluphethrcysserserglyargcysileserargasnphe130135140valcysasnglyglnaspaspcysseraspglyseraspgluleuasp145150155160cysalaproprothrcysglyalahisglupheglncysserthrser165170175sercysileproilesertrpvalcysaspaspaspalaaspcysser180185190aspglnseraspgluserleugluglncysglyargglnprovalile195200205histhrlyscysproalasergluileglncysglyserglyglucys210215220ilehislyslystrpargcysaspglyaspproaspcyslysaspgly225230235240seraspgluvalasncysproserargthrcysargproaspglnphe245250255glucysgluaspglysercysilehisglyserargglncysasngly260265270ileargaspcysvalaspglyseraspgluvalasncyslysasnval275280285asnglncysleuglyproglylysphelyscysargserglyglucys290295300ileaspileserlysvalcysasnglngluglnaspcysargasptrp305310315320seraspgluproleulysglucyshisileasnglucysleuvalasn325330335asnglyglycysserhisilecyslysaspleuvalileglytyrglu340345350cysaspcysalaalaglyphegluleuileasparglysthrcysgly355360365aspileaspglucysglnasnproglyilecysserglnilecysile370375380asnleulysglyglytyrlyscysglucysserargglytyrglnmet385390395400aspleualathrglyvalcyslysalavalglylysgluproserleu405410415ilephethrasnargargaspilearglysileglyleugluarglys420425430glutyrileglnleuvalgluglnleuargasnthrvalalaleuasp435440445alaaspilealaalaglnlysleuphetrpalaaspleuserglnlys450455460alailepheseralaserileaspasplysvalglyarghisvallys465470475480metileaspasnvaltyrasnproalaalailealavalasptrpval485490495tyrlysthriletyrtrpthraspalaalaserlysthrileserval500505510alathrleuaspglythrlysarglyspheleupheasnseraspleu515520525arggluproalaserilealavalaspproleuserglyphevaltyr530535540trpserasptrpglygluproalalysileglulysalaglymetasn545550555560glypheaspargargproleuvalthralaaspileglntrpproasn565570575glyilethrleuaspleuilelysserargleutyrtrpleuaspser580585590lysleuhismetleuserservalaspleuasnglyglnaspargarg595600605ilevalleulysserleuglupheleualahisproleualaleuthr610615620ilephegluaspargvaltyrtrpileaspglygluasnglualaval625630635tyrglyalaasnlysphethrglysergluleualathrleuvalasn645650655asnleuasnaspalaglnaspileilevaltyrhisgluleuvalgln660665670proserglylysasntrpcysglugluaspmetgluasnglyglycys675680685glutyrleucysleuproalaproglnileasnasphisserprolys690695700tyrthrcyssercysproserglytyrasnvalglugluasnglyarg705710715720aspcysglnserthralathrthrvalthrtyrsergluthrlysasp725730735thrasnserthrgluileseralathrserglyleuvalproglygly740745750ileasnvalthrthralavalsergluvalservalproprolysgly755760765thrseralaalatrpalaileleuproleuleuleuleuvalmetala770775780alavalglyglytyrleumettrpargasntrpglnhislysasnmet785790795800lyssermetasnpheaspasnprovaltyrleulysthrthrgluglu805810815aspleuserileaspileglyarghisseralaservalglyhisthr820825830tyrproalaileservalvalserthraspaspaspleuala835840845 ( 2 ) information for seq id no : 4 :( i ) sequence characteristics :( a ) length : 846 amino acids ( b ) type : amino acid ( c ) strandedness : single ( d ) topology : linear ( xi ) sequence description : seq id no : 4 : glylyslysalalyscysaspserserglnpheglncysthrasngly151015argcysilethrleuleutrplyscysaspglyaspgluaspcysala202530aspglyseraspglulysasncysvallyslysthrcysalagluser354045aspphevalcyslysasnglyglncysvalproasnargtrpglncys505560aspglyaspproaspcysgluasnglyseraspgluserproglugln65707580cyshismetargthrcysargileasngluilesercysglyalaarg859095serthrglncysileprovalsertrpargcysaspglygluasnasp100105110cysaspasnglygluaspglugluasncysglyasnilethrcysser115120125alaaspgluphethrcysserserglyargcysvalserargasnphe130135140valcysasnglyglnaspaspcysaspaspglyseraspgluleuasp145150155160cysalaproprothrcysglyalahisglupheglncysserthrser165170175sercysileproleusertrpvalcysaspaspaspalaaspcysser180185190aspglnseraspgluserleugluglncysglyargglnprovalile195200205histhrlyscysprothrsergluileglncysglyserglyglucys210215220ilehislyslystrpargcysaspglyaspproaspcyslysaspgly225230235240seraspgluvalasncysproserargthrcysargproaspglnphe245250255glucysgluaspglysercysilehisglyserargglncysasngly260265270ileargaspcysvalaspglyseraspgluvalasncyslysasnval275280285asnglncysleuglyproglylysphelyscysargserglyglucys290295300ileaspmetserlysvalcysaspglngluglnaspcysargasptrp305310315320seraspgluproleulysglucyshisileasnglucysleuvalasn325330335asnglyglycysserhisilecyslysaspleuvalileglytyrglu340345350cysaspcysalaalaglyphegluleuileasparglysthrcysgly355360365aspileaspglucysglnasnproglyilecysserglnilecysile370375380asnleulysglyglytyrlyscysglucysserargglytyrglnmet385390395400aspleualathrglyvalcyslysalavalglylysgluproserleu405410415ilephethrasnargargaspilearglysileglyleugluarglys420425430glutyrileglnleuvalgluglnleuargasnthrvalalaleuasp435440445alaaspilealaalaglnlysleuphetrpalaaspleuserglnlys450455460alailepheseralaserileaspasplysvalglyarghisphelys465470475480metileaspasnvaltyrasnproalaalailealavalasptrpval485490495tyrlysthriletyrtrpthraspalaalaserlysthrileserval500505510alathrleuaspglyalalysarglyspheleupheasnseraspleu515520525arggluproalaserilealavalaspproleuserglyphevaltyr530535540trpserasptrpglygluproalalysileglulysalaglymetasn545550555560glypheaspargargproleuvalthrgluaspileglntrpproasn565570575glyilethrleuaspleuvallysserargleutyrtrpleuaspser580585590lysleuhismetleuserservalaspleuasnglyglnaspargarg595600605ilevalleulysserleuglupheleualahisproleualaleuthr610615620ilephegluaspargvaltyrtrpileaspglygluasnglualaval625630635640tyrglyalaasnlysphethrglysergluleualathrleuvalasn645650655serleuasnaspalaglnaspileilevaltyrhisgluleuvalgln660665670proserglylysasntrpcysgluaspaspmetgluasnglyglycys675680685glutyrleucysleuproalaproglnileasnasphisserprolys690695700tyrthrcyssercysproasnglytyrasnleuglugluasnglyarg705710715720glucysglnserthrserthrprovalthrtyrsergluthrlysasp725730735ileasnthrthraspileleuargthrserglyleuvalproglygly740745750ileasnvalthrthralavalsergluvalservalproprolysgly755760765thrseralaalatrpalaileleuproleuleuleuleuvalmetala770775780alavalglyglytyrleumettrpargasntrpglnhislysasnmet785790795800lyssermetasnpheaspasnprovaltyrleulysthrthrgluglu805810815aspleuserileaspileglyarghisseralaservalglyhisthr820825830tyrproalaileservalvalserthraspaspaspleuala835840845__________________________________________________________________________