title: Structural insights into the pre-amyloid tetramer of β-2-microglobulin from covalent labeling and mass spectrometry.
abstract: The main pathogenic process underlying dialysis-related amyloidosis is the accumulation of β-2-microglobulin (β2m) as amyloid fibrils in the musculoskeletal system, and some evidence suggests that Cu(II) may play a role in β2m amyloid formation. Cu(II)-induced β2m fibril formation is preceded by the formation of discrete, oligomeric intermediates, including dimers, tetramers, and hexamers. In this work, we use selective covalent labeling reactions combined with mass spectrometry to investigate the amino acids responsible for mediating tetramer formation in wild-type β2m. By comparing the labeling patterns of the monomer, dimer, and tetramer, we find evidence that the tetramer interface is formed by the interaction of D strands from one dimer unit and G strands from another dimer unit. These covalent labeling data along with molecular dynamics calculations allow the construction of a tetramer model that indicates how the protein might proceed to form even higher-order oligomers.
authors: Department of Chemistry, University of Massachusetts, Amherst, Massachusetts 01003, USA.
authors: Vanessa Leah
authors: VL
authors: Mendoza
authors: Mario A
authors: MA
authors: Barón-Rodríguez
authors: Cristian
authors: C
authors: Blanco
authors: Richard W
authors: RW
authors: Vachet
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D002417:Cattle; D002645:Chickens; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D006736:Horses; D006801:Humans; D008027:Light; D055503:Protein Multimerization; D011498:Protein Precursors / Q000737:chemistry*; D012542:Scattering, Radiation; D021241:Spectrometry, Mass, Electrospray Ionization; D013194:Staining and Labeling; D053719:Tandem Mass Spectrometry; D001613:beta 2-Microglobulin / Q000737:chemistry*
chemical_list: D000682:Amyloid; D011498:Protein Precursors; D001613:beta 2-Microglobulin; D003300:Copper