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Domain Interactions Determine the Amyloidogenicity of Antibody Light Chain Mutants.

Abstract：

:In antibody light chain amyloidosis (AL), mutant light chains (LCs) or their variable domains (VLs) form fibrils, which accumulate in organs and lead to their failure. The molecular mechanism of this disease is still poorly understood. One of the key open issues is whether the mutant VLs and LCs differ in fibril formation. We addressed this question studying the effects of the VL mutations S20N and R61A within the isolated VL domain and in the full-length LC scaffold. Both VL variants readily form fibrils. Here, we find that in the LC context, the S20N variant is protected from fibril formation while for LC R61A fibril formation is even accelerated compared to VL R61A. Our analyses revealed that the partially unfolded state of the VL R61A domain destabilizes the CL domain by non-native interactions, in turn leading to a further unfolding of the VL domain. In contrast, the folded mutant VL S20N and VL wt form native interactions with CL. These are beneficial for LC stability and promote amyloid resistance. Thus the effects of specific mutations on the VL fold can have opposing effects on LC domain interactions, stability and amyloidogenicity.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Weber B,Hora M,Kazman P,Pradhan T,Rührnößl F,Reif B,Buchner J

doi

10.1016/j.jmb.2020.10.005

subject

Has Abstract

pub_date

2020-11-20 00:00:00

pages

6187-6199

issue

23

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(20)30578-7

journal_volume

432

pub_type

杂志文章

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