The Antibody Light-Chain Linker Is Important for Domain Stability and Amyloid Formation. Issue 22 (6th November 2015)

• Record Type: Journal Article
• Authors: Nokwe, Cardine N.; Hora, Manuel; Zacharias, Martin; Yagi, Hisashi; John, Christine; Reif, Bernd; Goto, Yuji; Buchner, Johannes
• Is Part Of: Journal of molecular biology. Volume 427:Issue 22(2015:Nov. 15)
• Page Start: 3572
• Page End: 3586
• Publication Date: 2015-11-06
• Subjects: ANS 1-anilino-8-naphthalene sulfonate -- GdmCl guanidinium chloride -- ThT thioflavin T -- CD circular dichroism -- NMR nuclear magnetic resonance -- MD molecular dynamics -- AL amyloid light-chain -- LC light chain -- HC heavy chain -- AUC analytical ultracentrifugation -- HSQC heteronuclear single quantum coherence -- EDTA ethylenediaminetetraacetic acid; protein folding and aggregation disease -- antibody light chain -- antibody amyloid -- domain stability -- immunoglobulin fold; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2015.09.012
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: The association of light chains (LCs) and heavy chains is the basis for functional antibodies that are essential for adaptive immune responses. However, in some cases, LCs and especially fragments consisting of the LC variable (VL ) domain are pathologically deposited in fatal aggregation diseases. The two domains of the LC are connected by a highly conserved linker. We show here that, unexpectedly, the linker residue Arg108 affects the conformational stability and folding of both VL κ and LC constant (CL κ) domains. Interestingly, the extension of VL by Arg108 results in its resistance to amyloid formation, which suggests that the nature of the truncation of the LC plays a crucial role in disease progression. Increased solvation due to the exposed charged C-terminal Arg108 residue explains its stabilizing effects on the VL domain. For the CL domain, the interaction of N-terminal loop residues with Arg108 is important for the integrity of the domain, as the disruption of this interaction results in fluctuation, partial opening of the protein's interior and the exposure of hydrophobic residues that destabilize the domain. This establishes new principles for antibody domain architecture and amyloidogenicity. Graphical abstract: Highlights: LC fragments involving parts of the linker connecting both domains are constituents of aggregates in LC amyloidosis. The linker residue Arg108 stabilizes both VL κ and CL κ domains and protects the VL κ from amyloid formation. Our findings reveal the importance of terminal residues for the integrity and amyloidogenicity of LC domains. This sheds new light on antibody domain architecture and amyloidogenicity.