Format

Send to

Choose Destination
Biochim Biophys Acta Mol Basis Dis. 2018 Jun;1864(6 Pt B):2294-2303. doi: 10.1016/j.bbadis.2017.12.009. Epub 2017 Dec 12.

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

Author information

1
Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.
2
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
3
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China; Jecho Laboratories, Inc., 7320A Executive Way, Frederick, MD 21704, USA.
4
Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA; Sackler Inst. of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
5
Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA. Electronic address: mabuyong@mail.nih.gov.

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.

KEYWORDS:

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

PMID:
29241665
PMCID:
PMC5927852
[Available on 2019-06-01]
DOI:
10.1016/j.bbadis.2017.12.009
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center