Spermadhesin, CUB domain superfamily

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 [8510165, 2026272]. 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 [17335815, 17051152]. Many CUB-containing proteins are peptidases belonging to MEROPS peptidase families M12A (astacin) and S1A (chymotrypsin). Proteins containing a CUB domain include:

• Mammalian complement subcomponents C1s/C1r, which form the calcium-dependent complex C1, the first component of the classical pathway of the complement system.
• Cricetidae sp. (Hamster) serine protease Casp, which degrades type I and IV collagen and fibronectin in the presence of calcium.
• Mammalian complement-activating component of Ra-reactive factor (RARF), a protease that cleaves the C4 component of complement.
• Vertebrate enteropeptidase , a type II membrane protein of the intestinal brush border, which activates trypsinogen.
• Vertebrate bone morphogenic protein 1 (BMP-1), a protein which induces cartilage and bone formation and expresses metalloendopeptidase activity.
• Sea urchin blastula proteins BP10 and SpAN.
• Caenorhabditis elegans hypothetical proteins F42A10.8 and R151.5.
• Neuropilin (A5 antigen), a calcium-independent cell adhesion molecule that functions during the formation of certain neuronal circuits.
• Fibropellins I and III from Strongylocentrotus purpuratus (Purple sea urchin).
• Mammalian hyaluronate-binding protein TSG-6 (or PS4), a serum and growth factor induced protein.
• Mammalian spermadhesins.
• Xenopus laevis embryonic protein UVS.2, which is expressed during dorsoanterior development.

Several of the above proteins consist of a catalytic domain together with several CUB domains interspersed by calcium-binding EGF domains. 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 [17446170].