title: Stability and aggregation propensity do not fully account for the association of various germline variable domain gene segments with light chain amyloidosis.
abstract: Variable domain (VL) gene segments exhibit variable tendencies to be associated with light chain amyloidosis (AL). While few of them are very frequent in AL and give rise to most of the amyloidogenic light chains compiled at the sequence databases, other are rarely found among the AL cases. To analyze to which extent these tendencies depend on folding stability and aggregation propensity of the germline VL protein, we characterized VL proteins encoded by four AL-associated germline gene segments and one not associated to AL. We found that the AL-associated germline rVL proteins differ widely in conformational stability and propensity to in vitro amyloid aggregation. While in vitro the amyloid formation kinetics of these proteins correlate well with their folding stabilities, the folding stability does not clearly correlate with their germline's frequencies in AL. We conclude that the association of the VL genes segments to amyloidosis is not determined solely by the folding stability and aggregation propensity of the germline VL protein. Other factors, such as the frequencies of destabilizing mutations and susceptibility to proteolysis, must play a role in determining the light chain amyloidogenicity.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Garay Sánchez
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Rodríguez Álvarez
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Zavala-Padilla
authors.forename: Luz María
authors.initials: LM
authors.lastname: Mejia-Cristobal
authors.forename: Armando
authors.initials: A
authors.lastname: Cruz-Rangel
authors.forename: Miguel
authors.initials: M
authors.lastname: Costas
authors.forename: D Alejandro
authors.initials: DA
authors.lastname: Fernández Velasco
authors.forename: Jorge
authors.initials: J
authors.lastname: Melendez-Zajgla
authors.forename: Luis
authors.identifier: 0000-0002-2551-0301
authors.initials: L
authors.lastname: Del Pozo-Yauner
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000235:genetics*; D000686:Amyloidosis / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D046529:Microscopy, Electron, Transmission; D066263:Protein Aggregation, Pathological / Q000235:genetics*; D000072417:Protein Domains; D055550:Protein Stability; D016415:Sequence Alignment; D013050:Spectrometry, Fluorescence
chemical_list: D000682:Amyloid; D007135:Immunoglobulin Variable Region