The CUB domain [1,2,E1] is an extracellular domain of approximately 110 residues which is found in functionally diverse, mostly developmentally regulated proteins. Almost all CUB domains contain four conserved cysteines which probably form two disulfide bridges (C1-C2, C3-C4). The structure of the CUB domain has been predicted to be a β-barrel similar to that of immunoglobulins.

Proteins that have been found to contain the CUB domain are listed below.

• Mammalian complement subcomponents C1s/C1r. C1q, C1s and C1r form the calcium-dependent complex C1, which is the first component of the classical pathway of the complement system. Both proteins contain two CUB domains, an EGF-like domain, two CCP domains and a trypsin family serine protease domain (see <PDOC00124>).
• Hamster serine protease Casp. Casp is a heterodimer of a regulatory and a catalytic chain which degrades type I and IV collagen and fibronectin in the presence of calcium. It shows the same modular architecture than C1s and C1r.
• Mammalian complement-activating component of Ra-reactive factor (RARF). This protein, also known as P100, is a protease that cleaves the C4 component of complement. It shows the same modular architecture than C1s and C1r.
• Vertebrate enteropeptidase (EC 3.4.21.9), a type II membrane protein of the intestinal brush border, which activates trypsinogen. It consists at least of a catalytic light chain and a multidomain heavy chain which has 2 LDL receptor-like domains, a MAM domain (see <PDOC00604>), a SRCR domain (see <PDOC00348>) and a CUB domain.
• Vertebrate bone morphogenic protein 1 (BMP-1), a protein which induces cartilage and bone formation and which expresses metalloendopeptidase activity. The Drosophila homolog of BMP-1 is the dorsal-ventral patterning protein Tolloid, which is required for normal dorsal development. In purple sea urchin a homolog protein is called SuBMP. All these molecules possess a zinc-metalloprotease domain (see <PDOC00129>) and a varying number of CUB (up to 5 in mouse BMP-1 and Tolloid) and EGF-like domains.
• Sea urchins blastula proteins BP10 and SpAN. Both proteins consist of 2 CUB domains, an EGF-like domain and a zinc-metalloprotease domain.
• Caenorhabditis elegans hypothetical proteins F42A10.8 and R151.5. Both proteins consist of a CUB domain, a EGF-like domain and a zinc- metalloprotease domain.
• Neuropilin (A5 antigen), a calcium-independent cell adhesion molecule that function during the formation of certain neuronal circuits. The sequence contains 2 CUB domains, 2 FA58C domains (see <PDOC00988>) and a MAM domain (see <PDOC00604>).
• Fibropellins I and III from sea urchin. These proteins form the apical lamina, a component of the extracellular matrix. These two proteins contain a CUB domain, followed by a variable number of EGF-like domains and a C- terminal avidin-like domain (see <PDOC00499>).
• Mammalian hyaluronate-binding protein TSG-6 (or PS4), a serum and growth factor induced protein possibly involved in cell-cell and cell-matrix interactions during inflammation and tumorgenesis. TSG-6 contains a 'link' domain followed by a CUB domain.
• Mammalian spermadhesins (see <PDOC00758>) which consist of a CUB domain.
• Xenopus embryonic protein UVS.2, which is expressed during dorsoanterior development. It contains 2 CUB domains.

For the sensitive detection of CUB domains, we have developed a profile which spans the whole domain.