title: Structural basis for the inhibition of truncated islet amyloid polypeptide aggregation by Cu(II): insights into the bioinorganic chemistry of type II diabetes.
abstract: Type 2 diabetes (T2D) is one of the most common chronic diseases, affecting over 300 million people worldwide. One of the hallmarks of T2D is the presence of amyloid deposits of human islet amyloid polypeptide (IAPP) in the islets of Langerhans of pancreatic β-cells. Recent reports indicate that Cu(II) can inhibit the aggregation of human IAPP, although the mechanism for this inhibitory effect is not clear. In this study, different spectroscopic techniques and model fragments of IAPP were employed to shed light on the structural basis for the interaction of Cu(II) with human IAPP. Our results show that Cu(II) anchors to His18 and the subsequent amide groups toward the C-terminal, forming a complex with an equatorial coordination mode 3N1O at physiological pH. Cu(II) binding to truncated IAPP at the His18 region is the key event for its inhibitory effect in amyloid aggregation. Electron paramagnetic resonance studies indicate that the monomeric Cu(II)-IAPP(15-22) complex differs significantly from Cu(II) bound to mature IAPP(15-22) fibers, suggesting that copper binding to monomeric IAPP(15-22) competes with the conformation changes needed to form β-sheet structures, thus delaying fibril formation. A general mechanism is proposed for the inhibitory effect of copper and other imidazole-binding metal ions in IAPP amyloid formation, providing further insights into the bioinorganic chemistry of T2D.
authors.affiliation: †Departamento de Química, Centro de Investigación y de Estudios Avanzados (Cinvestav), México, D.F., México.|‡Centro de Investigaciones Químicas, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos México.
authors.forename: Lina
authors.initials: L
authors.lastname: Rivillas-Acevedo
authors.affiliation: †Departamento de Química, Centro de Investigación y de Estudios Avanzados (Cinvestav), México, D.F., México.
authors.forename: Carolina
authors.initials: C
authors.lastname: Sánchez-López
authors.affiliation: ‡Centro de Investigaciones Químicas, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos México.
authors.forename: Carlos
authors.initials: C
authors.lastname: Amero
authors.affiliation: †Departamento de Química, Centro de Investigación y de Estudios Avanzados (Cinvestav), México, D.F., México.
authors.forename: Liliana
authors.initials: L
authors.lastname: Quintanar
mesh_terms: D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D015394:Molecular Structure; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000378:metabolism
chemical_list: D058228:Islet Amyloid Polypeptide; D066329:Protein Aggregates; D003300:Copper