6diy | pdb_00006diy

YTFGQ segment from Human Immunoglobulin Light-Chain Variable Domain, Residues 96-100, assembled as an amyloid fibril

spinqualitylabelsall models 6diy, resolution 0.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6diy is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Related: 6dix Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Systemic light chain amyloidosis (AL) is a human disease caused by overexpression of monoclonal immunoglobulin light chains that form pathogenic amyloid fibrils. These amyloid fibrils deposit in tissues and cause organ failure. Proteins form amyloid fibrils when they partly or fully unfold and expose segments capable of stacking into beta-sheets that pair and thereby form a tight, dehydrated interface. These structures, termed steric zippers, constitute the spines of amyloid fibrils. Here, using a combination of computational (with ZipperDB and Boston University ALBase), mutational, biochemical, and protein structural analyses, we identified segments within the variable domains of Ig light chains that drive the assembly of amyloid fibrils in AL. We demonstrate that there are at least two such segments and that each one can drive amyloid fibril assembly independently of the other. Our analysis revealed that peptides derived from these segments form steric zippers featuring a typical dry interface with high-surface complementarity and occupy the same spatial location of the Greek-key immunoglobulin fold in both lambda and kappa variable domains. Of note, some predicted stericzipper segments did not form amyloid fibrils or assembled into fibrils only when removed from the whole protein. We conclude that steric zipper propensity must be by experimentally validated and that the two segments identified here may represent therapeutic targets. In addition to elucidating the molecular pathogenesis of AL, these findings also provide an experimental approach for identifying segments that drive fibril formation in other amyloid diseases. Identification of two principal amyloid-driving segments in variable domains of Ig light chains in systemic light chain amyloidosis.,Brumshtein B, Esswein SR, Sawaya MR, Rosenberg G, Ly AT, Landau M, Eisenberg DS J Biol Chem. 2018 Oct 24. pii: RA118.004142. doi: 10.1074/jbc.RA118.004142. PMID:30355736 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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