title: The Antibody Light-Chain Linker Is Important for Domain Stability and Amyloid Formation.
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 VLκ and LC constant (CLκ) 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.
authors.affiliation: Center for Integrated Protein Science at the Department Chemie, Technische Universität München Lichtenbergstrasse 4, D-85747 Garching, Germany.
authors.forename: Cardine N
authors.initials: CN
authors.lastname: Nokwe
authors.affiliation: Center for Integrated Protein Science at the Department Chemie, Technische Universität München Lichtenbergstrasse 4, D-85747 Garching, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hora
authors.affiliation: Center for Integrated Protein Science at the Department Physik, Technische Universität München, James-Franck-Strasse 1, D-85748 Garching, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zacharias
authors.affiliation: Division of Protein Structural Biology, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yagi
authors.affiliation: Center for Integrated Protein Science at the Department Chemie, Technische Universität München Lichtenbergstrasse 4, D-85747 Garching, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: John
authors.affiliation: Center for Integrated Protein Science at the Department Chemie, Technische Universität München Lichtenbergstrasse 4, D-85747 Garching, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Reif
authors.affiliation: Division of Protein Structural Biology, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Goto
authors.affiliation: Center for Integrated Protein Science at the Department Chemie, Technische Universität München Lichtenbergstrasse 4, D-85747 Garching, Germany. Electronic address: johannes.buchner@tum.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Buchner
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000906:Antibodies / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007147:Immunoglobulin Light Chains / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D017510:Protein Folding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D057127:Single-Chain Antibodies / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D058227:Amyloidogenic Proteins; D000906:Antibodies; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D057127:Single-Chain Antibodies
keywords: antibody amyloid; antibody light chain; domain stability; immunoglobulin fold; protein folding and aggregation disease