page_title: Mannose 6-phosphate receptor
section_title: Structure
hierarchical_section_title: Mannose 6-phosphate receptor / Structure
caption_attribution_description: English: This is a PyMol generated image of the cation-dependent mannose 6-phosphate receptor displaying its ligand and the bound cation
context_page_description: The mannose 6-phosphate receptors are transmembrane glycoproteins that target enzymes to lysosomes in vertebrates.
  Mannose 6-phosphate receptors bind newly synthesized lysosomal hydrolases in the trans-Golgi network and deliver them to pre-lysosomal compartments. There are two different MPRs, one of ~300kDa and a smaller, dimeric receptor of ~46kDa. The larger receptor is known as the cation-independent mannose 6-phosphate receptor, while the smaller receptor requires divalent cations to efficiently recognize lysosomal hydrolases. While divalent cations are not essential for ligand binding by the human CD-MPR, the nomenclature has been retained.
  Both of these receptors bind terminal mannose 6-phosphate with similar affinity and have similar signals in their cytoplasmic domains for intracellular trafficking.
context_section_description: The CI-MPR and CD-MPR are structurally distinct receptors however they share an overall general structure as they are both type I integral membrane proteins. Both receptors have a large N-terminal extracytoplasmic domain, one transmembrane domain and a short C-terminal cytoplasmic tail. These cytoplasmic tails contain multiple sorting signals; some of which can be either phosphorylated or palmitoylated.
  CI-MPR: The CI-MPR is ~300 kDa. The N-terminal extracytoplasmic domain contains 15 contiguous P-type carbohydrate recognition domains. They are referred to as MRH (mannose 6-phosphate receptor homology) domains. The domains are homologous because they have:
  A similar size - each one has around 150 amino acid residues
  Conserved amino acid residues – between 14-38% sequence identity 
  Conserved positioning of 6 specific Cysteine residues that are involved in forming disulphide bonds 
  The structure of 7 out of the 15 domains has been determined, using X-ray crystallography, and they seem to share a similar fold. The CI-MPR exists mainly as a dimer in the membrane. Domains 3, 5 and 9 have been found to bind to mannose 6-phosphate. Domains 3 and 9 can bind to mannose 6-phosphate with high affinity. Domain 5 only binds Man-6-phosphate with a weak affinity. However domain 5 has also been shown to bind to the phosphodiester, Man-phosphate-GlcNAc. This is a safety mechanism for the cell – it means it is able to bind to lysosomal enzymes that have escaped the action of the enzyme that removes the GlcNAc residue. Combining these 3 domains allows the CI-MPR to bind to a wide range of phosphorylated glycan structures. Domain 11 binds to IGF-II.
  CD-MPR: The CD-MPR is much smaller than the CI-MPR – it is only ~46 kDa. Its N-terminal extracytoplasmic domain contains only 1 P-type carbohydrate recognition domain. The CD-MPR exists mainly as a dimer in the membrane. However monomeric and tetrameric forms are also thought to exist as well. The equilibrium between these different oligomers is affected by pH, temperature and presence of mannose 6-phosphate residues. Each monomer forms a 9 stranded ß-barrel which can bind to a single mannose 6-phosphate residue.
caption: The cation-dependent mannose 6-phosphate receptor with its ligand bound. The purple sphere represents the cation, Mn2+. Image generated from PDB file: = 1C39 1C39 using PyMol.
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