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).
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 (EC 18.104.22.168), 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.
- C. 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.
Human genes encoding proteins containing this domain include:
- ATRN, ATRNL1, BMP1,
- C1R, C1RL, C1S, CDCP2, CSMD1, CSMD2, CSMD3, CUBN, CUZD1,
- DCBLD1, DCBLD2, DMBT1, DREG,
- KREMEN1, KREMEN2,
- LRP10, LRP12, LRP3,
- MASP1, MASP2, MFRP,
- NETO1, NETO2, NRP1, NRP2,
- OVCH1, OVCH2,
- PCOLCE, PCOLCE2, PDGFC, PDGFD, PRSS7,
- SCUBE1, SCUBE2, SCUBE3, SEZ6, SEZ6L, SEZ6L2, ST14,
- TLL1, TLL2, TMPRSS7, TNFAIP6
- Bork P, Beckmann G (May 1993). "The CUB domain. A widespread module in developmentally regulated proteins". J. Mol. Biol. 231 (2): 539–45. doi:10.1006/jmbi.1993.1305. PMID 8510165.
- Bork P (April 1991). "Complement components C1r/C1s, bone morphogenic protein 1 and Xenopus laevis developmentally regulated protein UVS.2 share common repeats". FEBS Lett. 282 (1): 9–12. doi:10.1016/0014-5793(91)80433-4. PMID 2026272.
- Perry SE, Robinson P, Melcher A, Quirke P, Bühring HJ, Cook GP, Blair GE (March 2007). "Expression of the CUB domain containing protein 1 (CDCP1) gene in colorectal tumour cells". FEBS Lett. 581 (6): 1137–42. doi:10.1016/j.febslet.2007.02.025. PMID 17335815.
- Blanc G, Font B, Eichenberger D, Moreau C, Ricard-Blum S, Hulmes DJ, Moali C (June 2007). "Insights into how CUB domains can exert specific functions while sharing a common fold: conserved and specific features of the CUB1 domain contribute to the molecular basis of procollagen C-proteinase enhancer-1 activity". J. Biol. Chem. 282 (23): 16924–33. doi:10.1074/jbc.M701610200. PMID 17446170.