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Structure of the C1r-C1s interaction of the C1 complex of complement activation.

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posted on 24.01.2018, 12:23 by Jamal O. M. Almitairi, Umakhanth Venkatraman Girija, Christopher M. Furze, Xanthe Simpson-Gray, Farah Badakshi, Jamie E. Marshall, Wilhelm J. Schwaeble, Daniel A. Mitchell, Peter C. E. Moody, Russell Wallis
The multiprotein complex C1 initiates the classical pathway of complement activation on binding to antibody-antigen complexes, pathogen surfaces, apoptotic cells, and polyanionic structures. It is formed from the recognition subcomponent C1q and a tetramer of proteases C1r2C1s2 as a Ca2+-dependent complex. Here we have determined the structure of a complex between the CUB1-EGF-CUB2 fragments of C1r and C1s to reveal the C1r-C1s interaction that forms the core of C1. Both fragments are L-shaped and interlock to form a compact antiparallel heterodimer with a Ca2+ from each subcomponent at the interface. Contacts, involving all three domains of each protease, are more extensive than those of C1r or C1s homodimers, explaining why heterocomplexes form preferentially. The available structural and biophysical data support a model of C1r2C1s2 in which two C1r-C1s dimers are linked via the catalytic domains of C1r. They are incompatible with a recent model in which the N-terminal domains of C1r and C1s form a fixed tetramer. On binding to C1q, the proteases become more compact, with the C1r-C1s dimers at the center and the six collagenous stems of C1q arranged around the perimeter. Activation is likely driven by separation of the C1r-C1s dimer pairs when C1q binds to a surface. Considerable flexibility in C1s likely facilitates C1 complex formation, activation of C1s by C1r, and binding and activation of downstream substrates C4 and C4b-bound C2 to initiate the reaction cascade.

Funding

We thank Diamond Light Source (DLS) for access to beamlines I02, 103, and I04-1 and the UK Midlands Block Allocation Group mx14692, mx10369, and mx8359. We also thank beamline scientists at DLS for their help with data collection. Funding for this work was provided by the Medical Research Council (Grant G1000191/1, to R.W., P.C.E.M., and W.J.S.).

History

Citation

Proceedings of the National Academy of Sciences of the U. S. A., 2018, 115(4), pp. 768–773.

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Infection, Immunity and Inflammation

Version

VoR (Version of Record)

Published in

Proceedings of the National Academy of Sciences of the U. S. A.

Publisher

National Academy of Sciences

issn

0027-8424

eissn

1091-6490

Acceptance date

08/12/2017

Copyright date

2018

Available date

24/01/2018

Publisher version

http://www.pnas.org/content/115/4/768

Notes

Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.wwpdb.org (PDB ID codes 6F1C, 6F1H, 6F39, and 6F1D). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1718709115/-/DCSupplemental.

Language

en