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UCSD Molecule Pages

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The UCSD Signaling Gateway Molecule Pages, part of the Signaling Gateway project, provide essential information on over thousands of proteins involved in cellular signaling. Each Molecule Page contains regularly updated information derived from public data sources as well as sequence analysis, references and links to other databases. Published Molecule Pages contain an expert-authored review article that describes the biological activity, regulation and localization of the protein.

Issue cover


Inaugural issue of UCSD Molecule Pages

We are pleased to launch the inaugural issue of the

  UCSD Molecule Pages

. While the Molecule Pages themselves have been regularly published online since 2003, we have now taken a step ahead by compiling these publications in a bi-annual journal format.


Each Molecule Page, based on a cell signaling protein, combines expert authored reviews describing the biological activity, regulation and localization of the protein with curated, highly-structured data (e.g. protein interactions) and automatic annotation from publicly available data sources (e.g. UniProt and Genbank).




Cdc7 (Cell division cycle 7), also known as Hsk1 in fission yeast, is an important serine/threonine kinase, whose sequence is conserved from yeasts to mammals. The kinase activity of Cdc7 is regulated during the cell cycle by an activation subunit Dbf4 (also known as Dfp1/Him1 in fission yeast and ASK in mammals,) via heterodimer formation between the two. Cdc7 was first identified in budding yeast as a temperature-sensitive mutant (cdc7 ts ) defective in cell cycle progression. The budding yeast cdc7 ts cells arrest immediately before the onset of S phase at the non-permissive temperature, but resume growth and complete S phase in the absence of ongoing protein synthesis upon return to the permissive temperature. Cdc7 plays a conserved, pivotal role in triggering origin firing through phosphorylation of MCM (mini-chromosome maintenance) proteins. It facilitates the loading of Cdc45 and other replisome factors onto the pre-replicative complex, to generate active replication forks. In addition, it regulates other chromosomal transactions including DNA damage checkpoint, meiotic recombination, bypass DNA synthesis and histone functions. Selective induction of apoptosis in human cancer cells, but not in normal fibroblasts, after Cdc7 inhibition has provoked the effort in the development of Cdc7 inhibitors as potential anti-cancer drugs. Indeed, studies to date have suggested human Cdc7 as a new promising target in cancer therapy.

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WASP family verprolin-homologous protein 2 (WAVE2, also called WASF2) was originally identified by its sequence similarity at the carboxy-terminal VCA (verprolin, cofilin/central, acidic) domain with Wiskott-Aldrich syndrome protein (WASP) and N-WASP (neural WASP). In mammals, WAVE2 is ubiquitously expressed, and its two paralogs, WAVE1 (also called suppressor of cAMP receptor 1, SCAR1) and WAVE3, are predominantly expressed in the brain. The VCA domain of WASP and WAVE family proteins can activate the actin-related protein 2/3 (Arp2/3) complex, a major actin nucleator in cells. Proteins that can activate the Arp2/3 complex are now collectively known as nucleation-promoting factors (NPFs), and the WASP and WAVE families are a founding class of NPFs.

The WAVE family has an amino-terminal WAVE homology domain (WHD domain, also called the SCAR homology domain, SHD) followed by the proline-rich region that interacts with various Src-homology 3 (SH3) domain proteins. The VCA domain located at the C-terminus. WAVE2, like WAVE1 and WAVE3, constitutively forms a huge heteropentameric protein complex (the WANP complex), binding through its WHD domain with Abi-1 (or its paralogs, Abi-2 and Abi-3), HSPC300 (also called Brick1), Nap1 (also called Hem-2 and NCKAP1), Sra1 (also called p140Sra1 and CYFIP1; its paralog is PIR121 or CYFIP2).

The WANP complex is recruited to the plasma membrane by cooperative action of activated Rac GTPases and acidic phosphoinositides. Activated Rac indirectly associates with WAVE2 through Sra1 and/or insulin receptor tyrosine kinase substrate p53 (IRSp53). These interactions link Rac activation and the membrane recruitment of WAVE2. How acidic membrane phosphoinositides, including phosphatidylinositol-(4,5)-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol-(3,4,5)-triphosphate (PtdIns(3,4,5)P3), associate with the WANP complex is still unclear. However, purified monomeric WAVE2 binds directly to PtdIns(3,4,5)P3, and weakly to PtdIns(4,5)P2, through a basic amino acid cluster located just C-terminal to the WHD domain, suggesting that the interaction between the WANP complex and acidic phosphoinositides is mediated by WAVE proteins.

Binding of Rac and acidic phosphoinositides is also thought to activate the WANP complex at the plasma membrane. Cooperatively, tyrosine phosphorylation and serine/threonine phosphorylation of WAVE2 contribute to its activation. Although the precise mechanism of WANP complex activation remains to be elucidated, a plausible explanation is that the VCA domain, which is likely to be conformationally inhibited in the WANP complex, becomes released from the WANP complex following activation. The activated VCA domain can then simultaneously interact with the Arp2/3 complex and monomeric actin, leading to formation of an actin-nucleus-like core that is necessary to initiate actin polymerization.

Therefore, the WAVE family proteins mediate signals from Rac to the Arp2/3 to polymerize branched actin filaments in the vicinity of the plasma membrane enriched with PtdIns(4,5)P2 and PtdIns(3,4,5)P3. This signaling underlies Rac-induced formation of lamellipodial actin networks.

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Complement C3

Complement C3 is the central component of the human complement system. It is ~186 kDa in size, consisting of an α-chain (~110 kDa) and a β-chain (~75 kDa) that are connected by cysteine bridges. C3 in its native form is inactive. Cleavage of C3 into C3b (~177 kDa) and C3a (~9 kDa) is a crucial step in the complement activation cascade, which can be initiated by one or more of the three distinct pathways, called alternative, classical and lectin complement pathways. In the alternative pathway, hydrated C3 (C3(H20)) recruits complement factor B (fB), which is then cleaved by complement factor D (fD) to result in formation of the minor form of C3-convertase (C3(H20)Bb) that cleaves C3 into C3a and C3b. A small percent of the resulting C3b is rapidly deposited (opsonization through covalent bond) in the immediate vicinity of the site of activation (e.g. pathogen surface) and now forms the major form of C3-convertase (C3bBb), thereby creating an efficient cycle of C3 cleavage. Properdin, a positive regulator of the alternative pathway convertases, provides a hub for the assembly of C3bBb in addition to stabilization of the convertase. Classical and lectin pathways, when activated with recognition of pathogens or immune complexes use another C3-convertase (C4b2a) to cleave C3 into C3a and C3b. Although the three pathways are activated independently, they converge at C3 and use C3 as a substrate for their pathway specific C3-convertase: C3(H20)Bb, C3bBb or C4b2a. Further, C3b undergoes successive proteolytic cleavages by the regulatory complement factor I (fI) in presence of cofactors and lead to generation of iC3b (~174 kDa), C3d/C3dg (~33 kDa), C3c (~142 kDa) and C3f (~2 kDa). C3a is an anaphylatoxin while C3b is involved in opsonization of pathogens or apoptotic cells. Covalently bound C3b on pathogen/apoptotic cell surface is recognized by host immune cells through phagocytic (or complement component) receptors and induce subsequent immune response or directly target pathogen for clearance. The C3a fragment functions as a chemokine, and thereby recruits phagocytic and granulocytic cells to the sites of inflammation and cause strong pro-inflammatory signaling through their G-protein coupled receptors (GPCRs). As pathogen or apoptotic cell surface bound C3-convertases (C3bBb or C4b2a) can induce the amplification of the alternative pathway, this pathway might contribute to the major part of the complement activation process, even when initially triggered by the classical pathway and/or lectin pathway. Continuous activation of complement pathways shifts the substrate preference from C3 to C5 by formation of C5-convertase (formed by addition of C3b fragment to C3-convertases, C3(H20)Bb3b, C3bBb3b and C4b2a3b). C5-convertase activates C5, which by series of additional steps, promotes killing of target cell (pathogen) by pore formation.

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Complement C1q subcomponent subunit A

Complement C1q subcomponent subunit A (C1qA) is one of the three components of C1q molecule. Functional C1q is composed of eighteen polypeptide chains: six C1qA chains, six C1qB chains, and six C1qC chains, which are arranged as six heterotrimers of ABC: (ABC)6. Each of the individual C1q polypeptide chain consists of a N-terminal region and a C-terminal globular region (gC1q), of ~135 residues. Each N-terminal consists of 2-11 amino acid segments containing a half-cysteine residue that is involved in formation of inter-chain disulphide bonds, followed by a collagen-like region (CLR) consisting of ~81 residues. The collagen-like regions in A, B and C chains of each heterotrimer come together to form a triple helical collagen like structure. Further, A and B chains in each heterotrimer are bound by a disulphide bond, while C chain forms a disulphide bond with a C chain from the adjoining heterotrimer. Therefore the eighteen subunits come together to form six globular heads (gC1q), which are clusters of 3 independently folded C-terminal domains of the A, B and C chain. These globular domains recognize an array of self, non-self and altered-self ligands. C1q associates with the proenzymes C1r and C1s (2 molecules of each, in the molar ratio of 1:2:2 in a calcium dependent manner) to yield an active C1 complex, the first component of the serum complement system. C1r, upon binding of gC1q to an inciting stimulus, autoactivates itself and catalyzes breakage of a C1s ester bond, resulting in C1s activation and subsequent cleavage of C2 and C4 into their respective “a” and “b” fragments. Recognition of ligands by C1q molecule also defines C1q as a pattern recognition molecule (PRM). C1q recognizes distinct structures either directly on microbial structures and apoptotic cells, or indirectly after their recognition by antibodies or C-reactive protein (CRP). C1q in turn binds to multiple receptors (such as cC1qR (calreticulin), integrin α2β1 or other molecules on the surface of specific cell types of either myeloid or endothelial cell orgin) and shows regulated broad physiological functions beyond complement activation.

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Complement C5

Complement C5 is a 189 kDa protein synthesized in liver as a single-chain precursor molecule. The precursor molecule is then cleaved to a disulfide linked two-chain glycoprotein consisting of a 115 kDa (C5α) and a 75 kDa N-terminal (C5β) chain. C5 is present in all the three known complement activation pathways: classical, alternative and lectin. C5α chain is cleaved by C5 convertases, which are formed during the complement activation process, to form C5a (74 a.a long) and C5α' chain (925 a.a long). C5α' chain and C5β chain (655 a.a. long) together form C5b. C5a is a major anaphylotoxin involved in chemotaxis of neutrophils and release of pro-inflammatory cytokines. These functions of C5a require binding to its receptor, C5aR. C5b sequentially recruits C6, C7, C8 and C9 in a non-enzymatic manner to form the terminal complement complex (TCC, also called membrane attack complex or MAC). TCC forms a lytic pore in the target membrane and kills the pathogen. While the functions of C5a and C5b aid in killing the pathogen, they can also be responsible for generating an excess inflammatory response, which can damage host cells. Therefore, C5 functions are tightly regulated by interaction with other proteins in host. The regulatory proteins can either be host generated or pathogenic factors. Unregulated C5 function can result in disease phenotypes. Therapeutic antibodies against C5 are being developed with a view to treat these conditions.

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Complement factor H

Complement factor H (fH) is a single chain plasma glycoprotein (approximately 150 kDa in size), with 20 domains termed complement control protein (CCP) domains or short consensus repeats (SCR). The complement factor H gene (CFH) is located on chromosome 1q32 in the regulators of complement activation (RCA) gene cluster, adjacent to the genes that code for the Complement factor H-Related Proteins (CFHRs). The RCA cluster includes additional regulators containing SCR domains, such as C4 Binding Protein (C4BP), Complement receptor type 1 (CR1), Complement decay-accelerating factor (DAF), Membrane cofactor protein (MCP). fH and C4BP are fluid-phase (soluble) complement regulators, while the remaining are membrane-bound and all these regulators share similarities in their structure and function. fH prevents the formation of the alternative pathway C3 (C3bBb) and C5 (C3bBb3b) convertases. This inhibitory effect is either by competition with Complement factor B (fB) for C3b binding, by convertase decay acceleration activity or by acting as a cofactor for the Complement factor I (fI)-mediated degradation of C3b. Important targets for fH binding, in the neighborhood of C3b on host cells, are glycosaminoglycans and sialic acid (polyanionic molecules), which increase the affinity of fH for C3b. In addition to C3b and polyanionic molecules, fH also interacts with various endogenous molecules, such as pentraxins, extracellular matrix (ECM) proteins, prion protein, adrenomedullin, DNA, annexin-II and histones, to inhibit complement activation on certain host surfaces such as glomerular basement membrane, the extracellular matrix, and late apoptotic cells. CFH gene mutations and polymorphisms, and auto-antibodies against fH adversely affect regulatory and target recognition functions of fH. Some of the diseases associated with fH dysfunction are atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD; also termed membranoproliferative glomerulonephritis (MPGN) type II) and age-related macular degeneration (AMD). Interestingly, microbes and multicellular pathogens can recruit host fH to their surface in order to protect themselves from complement attack.

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