Fibril modelling by sequence and structure conservation analysis combined with protein docking techniques: beta(2)-microglobulin amyloidosis.
Obtaining atomic resolution structural models of amyloid fibrils is currently impossible, yet crucial for our understanding of the amyloid mechanism. Different pathways in the transformation of a native globular domain to an amyloid fibril invariably involve domain destabilization. Hence, locating the unstable segments of a domain is important for understanding its amyloidogenic transformation and possibly control it. Since relative conservation is suggested to relate to local stability, we performed an extensive, sequence and structure conservation analysis of the beta(2)-microglobulin (beta(2)-m) domain. Our dataset include 51 high resolution structures belonging to the "C1 set domain" family and 132 clustered PSI-BLAST search results. Segments of the beta(2)-m domain corresponding to strands A (residues 12-18), D (45-55) and G (91-95) were found to be less conserved and stable, while the central strands B (residues 22-28), C (36-41), E (62-70) and F (78-83) were found conserved and stable. Our findings are supported by accumulating observations from various experimental methods, including urea denaturation, limited proteolysis, H/D exchange and structure determination by both NMR and X-ray crystallography. We used our conservation findings together with experimental literature information to suggest a structural model for the polymerized unit of beta(2)-m. Pairwise protein docking and subsequent monomer stacking in the same manner suggest a fibril model consistent with the cross-beta structure.
Benyamini
Hadar
H
Bioinformatics Unit, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Gunasekaran
Kannan
K
Wolfson
Haim
H
Nussinov
Ruth
R
D000682:Amyloid / Q000096:biosynthesis*; D006801:Humans; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000378:metabolism
D000682:Amyloid; D001613:beta 2-Microglobulin