title: Near-planar solution structures of mannose-binding lectin oligomers provide insight on activation of lectin pathway of complement.
abstract: The complement system is a fundamental component of innate immunity that orchestrates complex immunological and inflammatory processes. Complement comprises over 30 proteins that eliminate invading microorganisms while maintaining host cell integrity. Protein-carbohydrate interactions play critical roles in both the activation and regulation of complement. Mannose-binding lectin (MBL) activates the lectin pathway of complement via the recognition of sugar arrays on pathogenic surfaces. To determine the solution structure of MBL, synchrotron x-ray scattering and analytical ultracentrifugation experiments showed that the carbohydrate-recognition domains in the MBL dimer, trimer, and tetramer are positioned close to each other in near-planar fan-like structures. These data were subjected to constrained modeling fits. A bent structure for the MBL monomer was identified starting from two crystal structures for its carbohydrate-recognition domain and its triple helical region. The MBL monomer structure was used to identify 10-12 near-planar solution structures for each of the MBL dimers, trimers, and tetramers starting from 900 to 6,859 randomized structures for each. These near-planar fan-like solution structures joined at an N-terminal hub clarified how the carbohydrate-recognition domain of MBL binds to pathogenic surfaces. They also provided insight on how MBL presents a structural template for the binding and auto-activation of the MBL-associated serine proteases to initiate the lectin pathway of complement activation.
authors.affiliation: Department of Structural and Molecular Biology, Darwin Building, University College London, Gower Street, London, WC1E 6BT, United Kingdom.
authors.forename: Ami
authors.initials: A
authors.lastname: Miller
authors.forename: Anna
authors.initials: A
authors.lastname: Phillips
authors.forename: Jayesh
authors.initials: J
authors.lastname: Gor
authors.forename: Russell
authors.initials: R
authors.lastname: Wallis
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Perkins
mesh_terms: D000818:Animals; D016466:CHO Cells; D037582:Complement Pathway, Mannose-Binding Lectin / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D037601:Mannose-Binding Lectin / Q000737:chemistry* / Q000378:metabolism; D055503:Protein Multimerization / Q000502:physiology*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D037601:Mannose-Binding Lectin