<p>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 [<cite idref="PUB00003306"/>, <cite idref="PUB00001610"/>]. 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 [<cite idref="PUB00035660"/>, <cite idref="PUB00035661"/>]. Many CUB-containing proteins are peptidases belonging to MEROPS peptidase families M12A (astacin) and S1A (chymotrypsin). Proteins containing a CUB domain include:</p><ul><li>Mammalian complement subcomponents C1s/C1r, which form the calcium-dependent complex C1, the first component of the classical pathway of the complement system.</li><li> <taxon tax_id="36483">Cricetidae sp.</taxon> (Hamster) serine protease Casp, which degrades type I and IV collagen and fibronectin in the presence of calcium.</li><li>Mammalian complement-activating component of Ra-reactive factor (RARF), a protease that cleaves the C4 component of complement.</li><li>Vertebrate enteropeptidase (<db_xref db="EC" dbkey="3.4.21.9"/>), a type II membrane protein of the intestinal brush border, which activates trypsinogen.</li><li>Vertebrate bone morphogenic protein 1 (BMP-1), a protein which induces cartilage and bone formation and expresses metalloendopeptidase activity.</li><li>Sea urchin blastula proteins BP10 and SpAN.</li><li> <taxon tax_id="6239">Caenorhabditis elegans</taxon> hypothetical proteins F42A10.8 and R151.5.</li><li>Neuropilin (A5 antigen), a calcium-independent cell adhesion molecule that functions during the formation of certain neuronal circuits.</li><li>Fibropellins I and III from <taxon tax_id="7668">Strongylocentrotus purpuratus</taxon> (Purple sea urchin).</li><li>Mammalian hyaluronate-binding protein TSG-6 (or PS4), a serum and growth factor induced protein.</li><li>Mammalian spermadhesins.</li><li> <taxon tax_id="8355">Xenopus laevis</taxon> embryonic protein UVS.2, which is expressed during dorsoanterior development.</li></ul><p>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 [<cite idref="PUB00035659"/>].</p> CUB