title: Amyloidogenic regions and interaction surfaces overlap in globular proteins related to conformational diseases.
abstract: Protein aggregation underlies a wide range of human disorders. The polypeptides involved in these pathologies might be intrinsically unstructured or display a defined 3D-structure. Little is known about how globular proteins aggregate into toxic assemblies under physiological conditions, where they display an initially folded conformation. Protein aggregation is, however, always initiated by the establishment of anomalous protein-protein interactions. Therefore, in the present work, we have explored the extent to which protein interaction surfaces and aggregation-prone regions overlap in globular proteins associated with conformational diseases. Computational analysis of the native complexes formed by these proteins shows that aggregation-prone regions do frequently overlap with protein interfaces. The spatial coincidence of interaction sites and aggregating regions suggests that the formation of functional complexes and the aggregation of their individual subunits might compete in the cell. Accordingly, single mutations affecting complex interface or stability usually result in the formation of toxic aggregates. It is suggested that the stabilization of existing interfaces in multimeric proteins or the formation of new complexes in monomeric polypeptides might become effective strategies to prevent disease-linked aggregation of globular proteins.
authors.affiliation: Departament de Bioquímica i Biologia Molecular and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Castillo
authors.forename: Salvador
authors.initials: S
authors.lastname: Ventura
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D011228:Prealbumin / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D007136:Immunoglobulins; D011228:Prealbumin; D001613:beta 2-Microglobulin; D013482:Superoxide Dismutase; D009113:Muramidase
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