Structure and energetic basis of overrepresented λ light chain in systemic light chain amyloidosis patients

Jun Zhao, Baohong Zhang, Jianwei Zhu, Ruth Nussinov, Buyong Ma

Research output: Contribution to journalArticlepeer-review

Abstract

Amyloid formation and deposition of immunoglobulin light-chain proteins in systemic amyloidosis (AL) cause major organ failures. While the κ light-chain is dominant (λ/κ = 1:2) in healthy individuals, λ is highly overrepresented (λ/κ = 3:1) in AL patients. The structural basis of the amyloid formation and the sequence preference are unknown. We examined the correlation between sequence and structural stability of dimeric variable domains of immunoglobulin light chains using molecular dynamics simulations of 24 representative dimer interfaces, followed by energy evaluation of conformational ensembles for 20 AL patients' light chain sequences. We identified a stable interface with displaced N-terminal residues, provides the structural basis for AL protein fibrils formation. Proline isomerization may cause the N-terminus to adopt amyloid-prone conformations. We found that λ light-chains prefer misfolded dimer conformation, while κ chain structures are stabilized by a natively folded dimer. Our study may facilitate structure-based small molecule and antibody design to inhibit AL. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang.

Original languageEnglish
Pages (from-to)2294-2303
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number6
DOIs
StatePublished - Jun 2018

Keywords

  • Aggregation
  • Amyloid
  • Antibody mis-folding
  • Energy landscape
  • Molecular dynamics
  • Protein misfolding
  • Systemic light chain amyloidosis

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