CUB domain

 
CUB domain is an evolutionarily conserved protein domain.
The CUB domain (for complement C1r/C1s, Uegf, Bmp1) is a structural motif of approximately 110 residues found almost exclusively in extracellular and plasma membrane-associated proteins, many of which are developmentally regulated. These proteins are involved in a diverse range of functions, including complement activation, developmental patterning, tissue repair, axon guidance and angiogenesis, cell signalling, fertilisation, haemostasis, inflammation, neurotransmission, receptor-mediated endocytosis, and tumour suppression. Many CUB-containing proteins are peptidases belonging to MEROPS peptidase families M12A (astacin) and S1A (chymotrypsin).
Examples.
Proteins containing a CUB domain include:
Several of the above proteins consist of a catalytic domain together with several CUB domains interspersed by calcium-binding EGF domains.
Spermadhesin is a subdivision of the CUB domain family and forms a major component of the mammalian seminal fluid. Spermadhesins are 110-133 amino acid polypeptides. The binding activity of spermadhesins, e.g. heparin and carbohydrate binding, enables their central role in promoting attachment of the spermatozoa to carbohydrate groups on the glycoproteins found on the surface of oocytes. The spermadhesins from pigs, bulls and stallions show 40-98% similarity in their amino acid sequences and all possess a disulphide bond between adjacent cysteine residues. The porcine spermadhesin polypeptides are coded by five closely linked genes. Bovine spermadhesin relies on a significantly lower number of genes with only two being associated with expression of this protein in bovine seminal fluid. Redundant genetic coding for spermadhesins have been observed in chimpanzees, dogs, and humans. The region correlating to spermadhesin genes in rat and mice DNA is void of any spermadhesin code. These variations in expression and genetic coding of spermadhesins are seen to result from evolutionary adjustments in genes as a consequence of mutations and deletions in genetic material.
Some CUB domains appear to be involved in oligomerisation and/or recognition of substrates and binding partners. For example, in the complement proteases, the CUB domains mediate dimerisation and binding to collagen-like regions of target proteins (e.g. C1q for C1r/C1s). The structure of CUB domains consists of a beta-sandwich with a jelly-roll fold. Almost all CUB domains contain four conserved cysteines that probably form two disulphide bridges (C1-C2, C3-C4). The CUB1 domains of C1s and Map19 have calcium-binding sites.
Human genes encoding proteins containing this domain include: