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Flexibility in Mannan-Binding Lectin-Associated Serine Proteases-1 and -2 Provides Insight on Lectin Pathway Activation
- Source :
- Structure(London, England:1993)
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- Summary 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.<br />Highlights • Ca2+-bound MASP crystal structures reveal binding sites for MBL and other ligands • The MASP crystal structures predict linear domain structures • Solution structures of MASP-1 and MASP-2 are bent by as much as 90° from linearity • Flexibility in MASP dimers may permit both intra- and inter-complex activation<br />Nan et al. show that MASPs, the serine proteases responsible for initiating the lectin pathway of complement activation, are much more flexible in solution than previously thought. This flexibility probably facilitates both intra- and inter-complex activation when mannan-binding lectin-MASP complexes bind to pathogen surfaces.
- Subjects :
- Models, Molecular
Protein Conformation, alpha-Helical
Cations, Divalent
Gene Expression
CHO Cells
lectin pathway
Crystallography, X-Ray
Article
Cricetulus
Structural Biology
Animals
Humans
complement
rat MASP
Protein Interaction Domains and Motifs
Amino Acid Sequence
Cloning, Molecular
Molecular Biology
Binding Sites
Sequence Homology, Amino Acid
Complement Pathway, Mannose-Binding Lectin
X-ray scattering
Recombinant Proteins
Rats
Mannose-Binding Protein-Associated Serine Proteases
Calcium
Protein Conformation, beta-Strand
atomistic modeling
analytical ultracentrifugation
Sequence Alignment
Protein Binding
Subjects
Details
- ISSN :
- 09692126
- Volume :
- 25
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Structure
- Accession number :
- edsair.pmid.dedup....97b26f2fc03ea9948f58337b4e15b01d
- Full Text :
- https://doi.org/10.1016/j.str.2016.12.014