title: Formation of amyloid fibers by monomeric light chain variable domains.
abstract: Systemic light chain amyloidosis is a lethal disease characterized by excess immunoglobulin light chains and light chain fragments composed of variable domains, which aggregate into amyloid fibers. These fibers accumulate and damage organs. Some light chains induce formation of amyloid fibers, whereas others do not, making it unclear what distinguishes amyloid formers from non-formers. One mechanism by which sequence variation may reduce propensity to form amyloid fibers is by shifting the equilibrium toward an amyloid-resistant quaternary structure. Here we identify the monomeric form of the Mcg immunoglobulin light chain variable domain as the quaternary unit required for amyloid fiber assembly. Dimers of Mcg variable domains remain stable and soluble, yet become prone to assemble into amyloid fibers upon disassociation into monomers.
authors.affiliation: From the Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA-Department of Energy (DOE) Institute for Genomics and Proteomics, UCLA, Los Angeles, California 90095 and.
authors.forename: Boris
authors.initials: B
authors.lastname: Brumshtein
authors.affiliation: From the Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA-Department of Energy (DOE) Institute for Genomics and Proteomics, UCLA, Los Angeles, California 90095 and.
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Esswein
authors.affiliation: From the Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA-Department of Energy (DOE) Institute for Genomics and Proteomics, UCLA, Los Angeles, California 90095 and.
authors.forename: Meytal
authors.initials: M
authors.lastname: Landau
authors.affiliation: the Pasarow Mass Spectrometry Laboratory, NPI-Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, California 90025.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Ryan
authors.affiliation: the Pasarow Mass Spectrometry Laboratory, NPI-Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, California 90025.
authors.forename: Julian P
authors.initials: JP
authors.lastname: Whitelegge
authors.affiliation: From the Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA-Department of Energy (DOE) Institute for Genomics and Proteomics, UCLA, Los Angeles, California 90095 and.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Phillips
authors.affiliation: From the Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA-Department of Energy (DOE) Institute for Genomics and Proteomics, UCLA, Los Angeles, California 90095 and.
authors.forename: Duilio
authors.initials: D
authors.lastname: Cascio
authors.affiliation: From the Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA-Department of Energy (DOE) Institute for Genomics and Proteomics, UCLA, Los Angeles, California 90095 and.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sawaya
authors.affiliation: From the Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA-Department of Energy (DOE) Institute for Genomics and Proteomics, UCLA, Los Angeles, California 90095 and david@mbi.ucla.edu.
authors.forename: David S
authors.initials: DS
authors.lastname: Eisenberg
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D007146:Immunoglobulin lambda-Chains / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary
chemical_list: D000682:Amyloid; D007135:Immunoglobulin Variable Region; D007146:Immunoglobulin lambda-Chains
keywords: Amyloid; Antibody; Bence-Jones Proteins; Light Chain Amyloidosis; Light Chain Variable Domains; Multiple Myeloma; Protein Aggregation; Systemic Amyloidosis; X-ray Crystallography