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

DOI: 10.1016/j.str.2016.12.014 DOI Help

Authors: Ruodan Nan (University College London) , Christopher M. Furze (University of Leicester) , David W. Wright (University College London) , Jayesh Gor (University College London) , Russell Wallis (University of Leicester) , Stephen J. Perkins (University College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure

State: Published (Approved)
Published: January 2017
Diamond Proposal Number(s): 8359 , 10369

Open Access Open Access

Abstract: 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 Ca2+-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.

Journal Keywords: analytical ultracentrifugation; complement; atomistic modeling; lectin pathway; rat MASP; X-ray scattering

Subject Areas: Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ESRF

Documents:
1-s2.0-S096921261630404X-main.pdf

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