TY - JOUR

T1 - Zinc determines dynamical properties and aggregation kinetics of human insulin

AU - Pounot, Kevin

AU - Grime, Geoffrey W.

AU - Longo, Alessandro

AU - Zamponi, Michaela

AU - Noferini, Daria

AU - Cristiglio, Viviana

AU - Seydel, Tilo

AU - Garman, Elspeth F.

AU - Weik, Martin

AU - Foderà, Vito

AU - Schirò, Giorgio

N1 - Funding Information: This work used the platforms of the Grenoble Instruct-ERIC Center (ISBG: UMS 3518 CNRS-CEA-UGA-EMBL) with support from FRISBI ( ANR-10-INSB-05-02 ) and GRAL ( ANR-10-LABX-49-01 ) within the Grenoble Partnership for Structural Biology (PSB). V.F. acknowledges Villum Fonden for the Villum Young Investigator Grant “Protein Superstructures as Smart Biomaterials (ProSmart)” 2018–2023 (project number: 19175 ). The electron microscope facility is supported by the Rhône-Alpes Region, Fondation Recherche Médicale (FRM) , and funds from FEDER , Centre National de la Recherche Scientifique (CNRS) , CEA , University of Grenoble , EMBL , and GIS-Infrastructures en Biologie Santé et Agronomie (IBISA) . The financial support provided by JCNS to perform neutron-scattering measurements at the Heinz Maier-Leibnitz Zentrum (MLZ), Garching, Germany, is gratefully acknowledged. Funding Information: We thank Daphna Fenel, Christine Moriscot, and Guy Schoehn from the Electron Microscopy platform; Caroline Mas and Marc Jamin for assistance and access to the Biophysical platform; and Aline Le Roy, Michel Th?paut, and Christine Ebel for assistance and access to the Protein Analysis Online platform. The access to Institut Laue-Langevin and ESRF beamlines to perform diffraction characterization is also acknowledged. This work used the platforms of the Grenoble Instruct-ERIC Center (ISBG: UMS 3518 CNRS-CEA-UGA-EMBL) with support from FRISBI (ANR-10-INSB-05-02) and GRAL (ANR-10-LABX-49-01) within the Grenoble Partnership for Structural Biology (PSB). V.F. acknowledges Villum Fonden for the Villum Young Investigator Grant ?Protein Superstructures as Smart Biomaterials (ProSmart)? 2018?2023 (project number: 19175). The electron microscope facility is supported by the Rh?ne-Alpes Region, Fondation Recherche M?dicale (FRM), and funds from FEDER, Centre National de la Recherche Scientifique (CNRS), CEA, University of Grenoble, EMBL, and GIS-Infrastructures en Biologie Sant? et Agronomie (IBISA). The financial support provided by JCNS to perform neutron-scattering measurements at the Heinz Maier-Leibnitz Zentrum (MLZ), Garching, Germany, is gratefully acknowledged. Publisher Copyright: © 2021 Biophysical Society

PY - 2021

Y1 - 2021

N2 - Protein aggregation is a widespread process leading to deleterious consequences in the organism, with amyloid aggregates being important not only in biology but also for drug design and biomaterial production. Insulin is a protein largely used in diabetes treatment, and its amyloid aggregation is at the basis of the so-called insulin-derived amyloidosis. Here, we uncover the major role of zinc in both insulin dynamics and aggregation kinetics at low pH, in which the formation of different amyloid superstructures (fibrils and spherulites) can be thermally induced. Amyloid aggregation is accompanied by zinc release and the suppression of water-sustained insulin dynamics, as shown by particle-induced x-ray emission and x-ray absorption spectroscopy and by neutron spectroscopy, respectively. Our study shows that zinc binding stabilizes the native form of insulin by facilitating hydration of this hydrophobic protein and suggests that introducing new binding sites for zinc can improve insulin stability and tune its aggregation propensity.

AB - Protein aggregation is a widespread process leading to deleterious consequences in the organism, with amyloid aggregates being important not only in biology but also for drug design and biomaterial production. Insulin is a protein largely used in diabetes treatment, and its amyloid aggregation is at the basis of the so-called insulin-derived amyloidosis. Here, we uncover the major role of zinc in both insulin dynamics and aggregation kinetics at low pH, in which the formation of different amyloid superstructures (fibrils and spherulites) can be thermally induced. Amyloid aggregation is accompanied by zinc release and the suppression of water-sustained insulin dynamics, as shown by particle-induced x-ray emission and x-ray absorption spectroscopy and by neutron spectroscopy, respectively. Our study shows that zinc binding stabilizes the native form of insulin by facilitating hydration of this hydrophobic protein and suggests that introducing new binding sites for zinc can improve insulin stability and tune its aggregation propensity.

U2 - 10.1016/j.bpj.2020.11.2280

DO - 10.1016/j.bpj.2020.11.2280

M3 - Journal article

C2 - 33545104

AN - SCOPUS:85100908222

VL - 120

SP - 886

EP - 898

JO - Biophysical Journal

JF - Biophysical Journal

SN - 0006-3495

IS - 5

ER -