6DIX

NFVFGT segment from Human Immunoglobulin Light-Chain Variable Domain, Residues 98-103, assembled as an amyloid fibril

6DIX の概要

• エントリーDOI: 10.2210/pdb6dix/pdb
• 分子名称: NFVFGT Immunoglobulin Light-Chain Variable Domain (2 entities in total)
• 機能のキーワード: amyloid fibril, protein fibril
• 由来する生物種: Homo sapiens
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 2735.01

構造登録者

Brumshtein, B.,Esswein, S.R.,Sawaya, M.R.,Eisenberg, D.S. (登録日: 2018-05-23, 公開日: 2018-10-31, 最終更新日: 2024-03-13)

主引用文献

Brumshtein, B.,Esswein, S.R.,Sawaya, M.R.,Rosenberg, G.,Ly, A.T.,Landau, M.,Eisenberg, D.S.
Identification of two principal amyloid-driving segments in variable domains of Ig light chains in systemic light-chain amyloidosis.
J. Biol. Chem., 293:19659-19671, 2018

PubMed Abstract: 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 β-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 λ and κ variable domains. Of note, some predicted steric-zipper 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 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.

PubMed: 30355736
DOI: 10.1074/jbc.RA118.004142

実験手法

X-RAY DIFFRACTION (1 Å)