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Open Access Publications from the University of California

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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.

Articles

MASP-2

MASP-2 (mannose/mannan binding lectin (MBL) associated serine protease-2) is a serum protein predominantly synthesized by the liver as a ~75kDa protein and is one of the key molecules of the innate immune system. It is mainly bound to multimeric protein complexes, such as MBL, the three ficolins (M-ficolin, L-ficolin and H-ficolin) and collectin kidney 1 (CL-K1, alias CL-11). These complexes serve as pathogen receptors, which are further bound to MASP-1, a serine protease. Binding of these complexes to their appropriate pathogenic ligands auto-activates MASP-1. Active MASP-1 in turn acts on its substrate, MASP-2, and thereby activates it. In a cascade of proteolytic cleavage events, MASP-2 activates complement proteins C4 and C2 to form C4b2a (classical C3 convertase), thereby converging the lectin pathway with the classical pathway of complement activation. Further, MASP-2 activity is regulated by several factors, including the serine protease inhibitor C1INH and by interaction with other proteins of the lectin complement pathway.

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MASP-1

MASP-1 (mannose/mannan binding lectin associated serine protease-1) is a serum protein (~79kDa poylpeptide) predominantly synthesized by the liver. It is an important player in the innate immune system and is mainly bound to multimeric pathogen recognition receptors such as mannose/mannan-binding lectin (MBL) and the three ficolins (M-ficolin, L-ficolin and H-ficolin). MASP-1 has two CUB, a calcium-binding EGF-like, a trypsin-like serine protease and two complement control protein (CCP) domains. The serine protease domain is auto-activated upon binding of these receptors to their appropriate pathogenic ligands, generally carbohydrate domains or acetylated sugar residues. MASP-1 is therefore a component of the lectin pathway of complement activation. The primary substrate for MASP-1 activity isMASP-2, another serine protease. MASP-2 in turn cleaves and activates complement proteins C4 and C2, thus converging the lectin pathway with the classical pathway of complement activation. MASP-1 activity is negatively regulated by the presence of alternate splice variants, MASP-3 and MAp44. MASP-1 by virtue of its serine protease activity, also plays a role in the coagulation pathway.

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MASP-3

MASP-3 (mannose/mannan binding lectin (MBL) associated serine protease-3) is ~82 kDa protein generated through alternative splicing of the MASP1 gene. This gene also generates MASP-1 and MAp44 proteins. MASP-3 is bound to multimeric forms of pathogen receptors, such as MBL and the three ficolins. MASP-3 has two CUB, a calcium-binding EGF-like, a trypsin-like serine protease and two complement control protein (CCP) domains. The serine protease domain however, is not known to be active and does not act on substrates of either MASP-1 or MASP-2. Instead, it competes with MASP-1 and MASP-2 to bind to MBL and therefore plays a regulatory role in the lectin pathway of complement activation. In mice however, MASP-3 can activate the alternative complement pathway, by directly activating complement factor D (fD).

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MAp44

MAp44 is a ~44 kDa alternate splice product of MASP1 and is mainly expressed in the heart. Mannose/mannan binding lectin (MBL) associated serine proteases, MASP-1 and MASP-3 are other products of MASP1. Similar to MASP-1 (isoform 1 of MASP1, which represents the longest transcript), MAp44 has a C1r/C1s/Uegf/bmp1 (CUB) domain, calcium-binding EGF-like domain and complement control protein (CCP) domains. However, it lacks the serine protease domain of MASP-1 and therefore cannot perform MASP-1's functions. MAp44 binds to multimeric pathogen receptors such asMBL and the three ficolins, and is believed to play a regulatory role in the lectin pathway of complement activation.

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H-Ficolin

H-ficolin is a serum lectin synthesized (as a ~34 kDa polypeptide) predominantly by the liver and lung tissues and is one of the soluble pattern recognition receptors of the innate immune system. It is structurally similar to L- and M- ficolins, but is different in its tissue expression and binding affinities to pathogenic ligands. Ficolins have an amino (N)-terminal cysteine-rich region, a middle stretch of a collagen-like sequence, and a fibrinogen-like domain in the carboxy (C)-terminus. Three identical polypeptides form a structural (triple helical) subunit, with the help of the collagen-like domain. Further oligomerization of this subunit results in different sized H-ficolin molecules in circulation. The polypeptides in the structural subunit are cross-linked by disulphide bonds in the N-terminal region and the fibrinogen-like domain forms a globular structure. Thus, the overall structure of H-ficolin also resembles mannose/mannan- binding lectin (MBL). The primary role of H-ficolin is that of a pattern recognition receptor, recognizing acetylated sugar residues on the cell surface of different bacteria, viruses and other pathogens. There are two pathways by which H-ficolin may participate in a host defense response: 1) It activates the complement lectin pathway, via MBL/ficolin associated serine proteases (MASPs), that converges with the classical complement pathway at the level of complement C4, and 2) it may also act directly as an opsonin, enhancing phagocytosis by binding to cell-surface receptors present on phagocytic cells.

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Integrin beta-2

Integrins are heterodimeric transmembrane (TM) glycoproteins containing one each of α and β subunit, which are held together by non-covalent forces. Integrin β2 (CD18) is the β subunit for four heterodimers: αDβ2, αXβ2, αMβ2 and αLβ2. Integrin β2 family plays an essential role in leukocyte recruitment and activation during inflammation. Structurally, while most part of the αβ dimer is extracellular, both the subunits traverse the plasma membrane and terminate as short cytoplasmic domains. Each heterodimeric integrin exists on the cell surface mainly in an inactive (bent) form until they receive stimulating signals from other receptors (via inside-out signaling), and the end result of integrin activation is a shift in integrin conformation from a bent to an extended one. The binding of cytoplasmic proteins to α- and/or β-subunit carboxy-terminal tails is an essential part of the activation process, as these interactions stabilize the extended integrin conformation and provide connections to the cytoskeleton. The binding of extracellular ligand to the extended form of integrin (via outside-in signaling) triggers a large variety of signal transduction events that modulate cell behaviors such as adhesion, proliferation, survival or apoptosis, shape, polarity, motility, and differentiation, mostly through effects on the cytoskeleton. The receptors αMβ2 (Complement Receptor type 3, CR3) and αXβ2 (Complement Receptor type 4, CR4) are regarded to be the most important mediators for complement-driven phagocytosis.

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Complement C2

Complement C2 is a single chain serum glycoprotein (110 kDa), which serves as the catalytic subunit of C3 and C5 convertases in the classical and lectin pathways. During complement activation, C2 is cleaved by classical (C1s) or lectin (MBL-associated serine protease-2; MASP-2) proteases into two fragments: C2b and C2a. C2a, a serine protease, in complex with C4b fragment of complement factor C4, generates the C3 (C4b2a) or C5 (C4b2a3b) convertase. C3 convertase is very short-lived and cleaves complement C3 into C3a and C3b fragments (selective cleavage of Arg-|-Ser bond in C3 alpha-chain). C3 convertase requires the presence of magnesium and decays over time at physiologic temperatures. However, 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 convertase i.e. C4b2a3b). C5 convertase cleaves complement C5 to become activated into C5a and C5b fragments (selective cleavage of Arg-|-Xaa bond in C5 alpha-chain) and by a series of additional steps, promotes lysis of bacteria and damaged cells by pore or membrane attack complex (MAC) formation. Deficiency of C2 has been reported to be associated with certain autoimmune diseases. Single nucleotide polymorphisms (SNPs) in the C2 gene have been associated with altered susceptibility to age-related macular degeneration.

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