In:
Proteins: Structure, Function, and Bioinformatics, Wiley, Vol. 80, No. 8 ( 2012-08), p. 1987-1997
Abstract:
Complement is an important part of the immune system. It is initiated through three different pathways known as the classical, lectin, and alternative pathway. The multimolecular C1 complex of the classical pathway consists of a subcomponent, C1q, which binds to a tetramer comprising two C1r and two C1s proteases. A detailed description of the structure of the C1 complex is essential to fully understand how the complex acts on pathogens. A variety of different models have been proposed, which differ mainly in the way the proteases interact with C1q. In this study, we have used a combination of homology‐based structure prediction and molecular dynamics to predict a partial structure of the C1s/C1r/C1r/C1s tetramer. For computational expediency the study was restricted to the CUB 1 ‐EGF‐CUB 2 domains which are directly involved in the formation of the tetramer and its interaction with C1q; the catalytic fragments (CCP 1 ‐CCP 2 ‐SP), which mediate C1 activation and subsequent cleavage of substrates, were omitted. A systematic molecular dynamics (MD) study of several possible dimeric combinations suggest that the tetramer is formed when a pair of C1r/C1s dimers form a “doughnut” via a C1s/C1s head‐to‐tail interaction, which is stabilized by several putative salt bridges at the dimer interface. This result is consistent with biochemical data which have shown that self assembly requires the formation of C1r‐C1s contacts and that electrostatic interactions play a key role. Furthermore, it identifies a number of putative binding residues that can be tested using site‐directed mutagenesis. Proteins 2012. © 2012 Wiley Periodicals, Inc
Type of Medium:
Online Resource
ISSN:
0887-3585
,
1097-0134
Language:
English
Publisher:
Wiley
Publication Date:
2012
detail.hit.zdb_id:
1475032-6
SSG:
12
