Molecular Determinants of the Substrate Specificity of the Complement-initiating Protease, C1r

Abstract

Background: Classical complement pathway activation depends on cleavage of inactive C1s by C1r. Results: P2 Gln and P1Ј Ile residues in activation loop of C1s are crucial for activation by C1r. Conclusion: Residues at P2 and P1Ј in cleavage position of C1s make important interactions with C1r active site. Significance: Critical determinants identified for activation of the classical complement pathway.

The X-ray Crystal Structure of Mannose-binding Lectin-associated Serine Proteinase-3 Reveals the Structural Basis for Enzyme Inactivity Associated with the Carnevale, Mingarelli, Malpuech, and Michels (3MC) Syndrome

“…The Activity and Specificity of Activated MASP-3-We used a mutant of MASP-3 in which a Gln residue had been introduced at position 448 in place of the Lys residue at that position to facilitate its efficient cleavage and activation by C1r (20) (Fig. 1).…”

“…This enzyme could be efficiently cleaved and activated by the C1r protease of the classical pathway complement (20). Because the amino acid sequence C-terminal to the activation bond represents that of the wild type MASP-3, the C1r-activated recombinant M3Q protein contains a fully functional SP domain of the wild type MASP-3.…”

“…In a previous study (20), we produced a form of human MASP-3 with a single Gln residue replacing the Lys residue N-terminal to the R-I activation bond (M3Q). This enzyme could be efficiently cleaved and activated by the C1r protease of the classical pathway complement (20).…”

Reincarnation of ancient links between coagulation and complement

“…C1-INH binds to and inactivates several complement-related proteases, including C1r and C1s of the CP, and MASP1 and MASP2 of the LP, thereby preventing formation of the CP/LP convertases. Its inhibitory activity is potentiated by polyanions, that is, heparin [7,14]. By the same mechanism, C1-INH also interferes with factor XIa, factor XIIa, and kallikrein, dampening coagulation activation via the con- Multimeric strings support platelet adhesion/aggregation Activating surface for assembly of alternative pathway convertase VWF von Willebrand factor tact pathway and reducing pro-inflammatory effects of kallikrein.…”

Genome-wide pathway analysis in amyotrophic lateral sclerosis

“…There is increasing evidence that the development of mental and neurologic disorders, including ALS, is related to complex pathways involving the immune system and inflammatory response (Pardo et al, 2005;Dantzer et al, 2008). The C1r B chain is a serine protease that combines with C1q and C1s to form C1, the first component of the classical pathway of the complement system (Wijeyewickrema et al, 2013). Mannan-binding lectin serine peptidase 2 (MASP2) plays an important role in the activation of the complement system via mannose-binding lectin (Duncan et al, 2012).…”