8w18 | pdb_00008w18
The crystal structure of the Michaelis-Menten complex of a C1s/C1-INH at 3.94 Angstroms
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 ancient arm of innate immunity known as the complement system is a blood proteolytic cascade involving dozens of membrane-bound and solution-phase components. Although many of these components serve as regulatory molecules to facilitate controlled activation of the cascade, C1 esterase inhibitor (C1-INH) is the sole canonical complement regulator belonging to a superfamily of covalent inhibitors known as serine protease inhibitors (SERPINs). In addition to its namesake role in complement regulation, C1-INH also regulates proteases of the coagulation, fibrinolysis, and contact pathways. Despite this, the structural basis for C1-INH recognition of its target proteases has remained elusive. In this study, we present the crystal structure of the Michaelis-Menten (M-M) complex of the catalytic domain of complement component C1s and the SERPIN domain of C1-INH at a limiting resolution of 3.94 A. Analysis of the structure revealed that nearly half of the protein/protein interface is formed by residues outside of the C1-INH reactive center loop. The contribution of these residues to the affinity of the M-M complex was validated by site-directed mutagenesis using surface plasmon resonance. Parallel analysis confirmed that C1-INH-interfacing residues on C1s surface loops distal from the active site also drive affinity of the M-M complex. Detailed structural comparisons revealed differences in substrate recognition by C1s compared with C1-INH recognition and highlight the importance of exosite interactions across broader SERPIN/protease systems. Collectively, this study improves our understanding of how C1-INH regulates the classical pathway of complement, and it sheds new light on how SERPINs recognize their cognate protease targets. The Crystal Structure of the Michaelis-Menten Complex of C1 Esterase Inhibitor and C1s Reveals Novel Insights into Complement Regulation.,Garrigues RJ, Garrison MP, Garcia BL J Immunol. 2024 Jul 12:ji2400194. doi: 10.4049/jimmunol.2400194. PMID:38995166[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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