4j1y
The X-ray crystal structure of human complement protease C1s zymogen
Structural highlights
DiseaseC1S_HUMAN Defects in C1S are the cause of complement component C1s deficiency (C1SD) [MIM:613783. A rare defect resulting in C1 deficiency and impaired activation of the complement classical pathway. C1 deficiency generally leads to severe immune complex disease with features of systemic lupus erythematosus and glomerulonephritis. FunctionC1S_HUMAN C1s B chain is a serine protease that combines with C1q and C1r to form C1, the first component of the classical pathway of the complement system. C1r activates C1s so that it can, in turn, activate C2 and C4. Publication Abstract from PubMedThe complement system is an ancient innate immune defense pathway that plays a front-line role in eliminating microbial pathogens. Recognition of foreign targets by antibodies drives sequential activation of two serine proteases, C1r and C1s, which reside within the complement Component 1 (C1) complex. Active C1s propagates the immune response through its ability to bind and cleave the effector molecule complement Component 4 (C4). Currently, the precise structural and biochemical basis for the control of the interaction between C1s and C4 is unclear. Here, using surface plasmon resonance, we show that the transition of the C1s zymogen to the active form is essential for C1s binding to C4. To understand this, we determined the crystal structure of a zymogen C1s construct [comprising two Complement Control Protein (CCP) domains and the serine protease (SP) domain]. These data reveal that two loops (492-499 and 573-580) in the zymogen SP domain adopt a conformation that would be predicted to sterically abrogate C4 binding. The transition from zymogen to active C1s repositions both loops such that they would be able to interact with sulfotyrosine residues on C4. The structure also shows the junction of the CCP1 and CCP2 domains of C1s for the first time, yielding valuable information about the exosite for C4 binding located at this position. Together, these data provide a structural explanation for the control of the interaction with C1s and C4 and, furthermore, point to alternative strategies for developing therapeutic approaches for controlling activation of the complement cascade. A molecular switch governs the interaction between human complement protease C1s and its substrate, complement C4.,Perry AJ, Wijeyewickrema LC, Wilmann PG, Gunzburg MJ, D'Andrea L, Irving JA, Pang SS, Duncan RC, Wilce JA, Whisstock JC, Pike RN J Biol Chem. 2013 Apr 16. PMID:23592783[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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