title: Amyloid formation by human carboxypeptidase D transthyretin-like domain under physiological conditions.
abstract: Protein aggregation is linked to a growing list of diseases, but it is also an intrinsic property of polypeptides, because the formation of functional globular proteins comes at the expense of an inherent aggregation propensity. Certain proteins can access aggregation-prone states from native-like conformations without the need to cross the energy barrier for unfolding. This is the case of transthyretin (TTR), a homotetrameric protein whose dissociation into its monomers initiates the aggregation cascade. Domains with structural homology to TTR exist in a number of proteins, including the M14B subfamily carboxypeptidases. We show here that the monomeric transthyretin-like domain of human carboxypeptidase D aggregates under close to physiological conditions into amyloid structures, with the population of folded but aggregation-prone states being controlled by the conformational stability of the domain. We thus confirm that the TTR fold keeps a generic residual aggregation propensity upon folding, resulting from the presence of preformed amyloidogenic β-strands in the native state. These structural elements should serve for functional/structural purposes, because they have not been purged out by evolution, but at the same time they put proteins like carboxypeptidase D at risk of aggregation in biological environments and thus can potentially lead to deposition diseases.
authors.affiliation: From the Institut de Biotecnologia i Biomedicina, Departaments de Bioquimica i Biologia Molecular and.
authors.forename: Javier
authors.initials: J
authors.lastname: Garcia-Pardo
authors.affiliation: From the Institut de Biotecnologia i Biomedicina, Departaments de Bioquimica i Biologia Molecular and.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Graña-Montes
authors.affiliation: From the Institut de Biotecnologia i Biomedicina, Departaments de Bioquimica i Biologia Molecular and.
authors.forename: Marc
authors.initials: M
authors.lastname: Fernandez-Mendez
authors.affiliation: From the Institut de Biotecnologia i Biomedicina.
authors.forename: Angels
authors.initials: A
authors.lastname: Ruyra
authors.affiliation: From the Institut de Biotecnologia i Biomedicina, Biologia Cel·lular, Immunologia i Fisiologia Animal, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Roher
authors.affiliation: From the Institut de Biotecnologia i Biomedicina, Departaments de Bioquimica i Biologia Molecular and.
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Aviles
authors.affiliation: From the Institut de Biotecnologia i Biomedicina, Departaments de Bioquimica i Biologia Molecular and julia.lorenzo@uab.es.
authors.forename: Julia
authors.initials: J
authors.lastname: Lorenzo
authors.affiliation: From the Institut de Biotecnologia i Biomedicina, Departaments de Bioquimica i Biologia Molecular and salvador.ventura@uab.es.
authors.forename: Salvador
authors.initials: S
authors.lastname: Ventura
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D066329:Protein Aggregates; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D000682:Amyloid; D011228:Prealbumin; D066329:Protein Aggregates; D011506:Proteins; D011994:Recombinant Proteins; C094315:metallocarboxypeptidase D
keywords: Amyloid; Carboxypeptidase; Protein Aggregation; Protein Misfolding; Protein Stability; Transthyretin