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Flexibility in Mannan-Binding Lectin-Associated Serine Proteases-1 and -2 Provides Insight on Lectin Pathway Activation.

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journal contribution
posted on 07.02.2017, 09:47 by R. Nan, Christopher M. Furze, D. W. Wright, J. Gor, Russell Wallis, S. J. Perkins
The lectin pathway of complement is activated by complexes comprising a recognition component (mannose-binding lectin, serum ficolins, collectin-LK or collectin-K1) and a serine protease (MASP-1 or MASP-2). MASP-1 activates MASP-2, and MASP-2 cleaves C4 and C4b-bound C2. To clarify activation, new crystal structures of Ca(2+)-bound MASP dimers were determined, together with their solution structures from X-ray scattering, analytical ultracentrifugation, and atomistic modeling. Solution structures of the CUB1-EGF-CUB2 dimer of each MASP indicate that the two CUB2 domains were tilted by as much as 90° compared with the crystal structures, indicating considerable flexibility at the EGF-CUB2 junction. Solution structures of the full-length MASP dimers in their zymogen and activated forms revealed similar structures that were much more bent than anticipated from crystal structures. We conclude that MASP-1 and MASP-2 are flexible at multiple sites and that this flexibility may permit both intra- and inter-complex activation.

Funding

R.N. was supported by an MRC grant (MR/K011715/1). D.W.W. was supported by the CCP-SAS project, a joint EPSRC (EP/K039121/1) and NSF (CHE-1265821) grant. R.W. is a member of the Midland Block Allocation Group for access to Diamond Light Source (allocation grants MX8359 and MX10369). Open Access funded by Medical Research Council

History

Citation

Structure, 2017 25, 1–12

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation

Version

VoR (Version of Record)

Published in

Structure

Publisher

Elsevier (Cell Press)

issn

0969-2126

eissn

1878-4186

Acceptance date

21/12/2016

Available date

07/02/2017

Publisher version

http://www.sciencedirect.com/science/article/pii/S096921261630404X

Notes

Supplemental Information includes Supplemental Experimental Procedures, two figures, one table, and six pdb files and can be found with this article online at http://dx.doi.org/10.1016/j.str.2016.12.014.

Language

en