title: Inhibitory Mechanism of Epigallocatechin Gallate on Fibrillation and Aggregation of Amidated Human Islet Amyloid Polypeptide.
abstract: The abnormal fibrillation of human islet amyloid polypeptide (hIAPP) is associated with development of type II diabetes mellitus (T2DM). (-)-Epigallocatechin gallate (EGCG) can bind amyloid proteins to inhibit the fibrillation of these proteins. However, the mechanic detail of EGCG inhibiting amyloid formation is still unclear at the molecular level. In the present work, we sought to investigate the effect of EGCG on amidated hIAPP (hIAPP-NH2) fibrillation and aggregation by using spectroscopic and microscopic techniques, and also sought to gain insights into the interaction of EGCG and hIAPP22-27by using spectroscopic experiments and quantum chemical calculations. ThT fluorescence, real-time NMR, and TEM studies demonstrated that EGCG inhibits the formation of hIAPP-NH2fibrils, while promoting the formation of hIAPP-NH2amorphous aggregates. Phenylalanine intrinsic fluorescence and NMR studies of the EGCG/hIAPP22-27complex revealed three important binding sites including the A ring of EGCG, residue Phe23, and residue Ile26. DFT calculations identified the dominant binding structures of EGCG/Phe23 and EGCG/Ile26 complexes, named structure I and structure II, respectively. Our study demonstrates the inhibitory mechanism of EGCG on fibrillation and aggregation of hIAPP-NH2in which EGCG interacts with hIAPP-NH2through hydrogen bonding and π-π interactions between the A ring and residue Phe23 as well as hydrophobic interactions between the A ring and residue Ile26, which can thus inhibit the interpeptide interaction between hIAPP-NH2monomers and finally inhibit fibrillation of hIAPP-NH2. This study agrees with and reinforces previous studies and offers an intuitive explanation at both the atomic and molecular levels. Our findings may provide an invaluable reference for the future development of new drugs in the management of diabetes.
authors.affiliation: State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai, 200433, P. R. China), Fax: (+86) 21-55664038.
authors.forename: Zhi-Xue
authors.initials: ZX
authors.lastname: Xu
authors.affiliation: Collaborative Innovation Center of Chemistry for Energy Material, Shanghai Key Laboratory of Molecular Catalysis & Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, P. R. China.
authors.forename: Gong-Li
authors.initials: GL
authors.lastname: Ma
authors.affiliation: Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, P. R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai, 200433, P. R. China), Fax: (+86) 21-55664038.
authors.forename: Cong-Heng
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, P. R. China.
authors.forename: Yan-Ming
authors.initials: YM
authors.lastname: He
authors.affiliation: State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai, 200433, P. R. China), Fax: (+86) 21-55664038.
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai, 200433, P. R. China), Fax: (+86) 21-55664038.
authors.forename: Guang-Rong
authors.initials: GR
authors.lastname: Zhou
authors.affiliation: Collaborative Innovation Center of Chemistry for Energy Material, Shanghai Key Laboratory of Molecular Catalysis & Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, P. R. China.
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Li
authors.affiliation: Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, P. R. China.
authors.forename: Hong-Jie
authors.initials: HJ
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai, 200433, P. R. China), Fax: (+86) 21-55664038.
authors.forename: Ping
authors.identifier: http://orcid.org/0000-0002-5954-7655
authors.initials: P
authors.lastname: Zhou
mesh_terms: D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000187:drug effects*; D015394:Molecular Structure; D066329:Protein Aggregates / Q000187:drug effects
chemical_list: D058228:Islet Amyloid Polypeptide; D066329:Protein Aggregates; D002392:Catechin; C045651:epigallocatechin gallate
keywords: epigallocatechin gallate; human islet amyloid polypeptide; hydrophobic interactions; quantum chemical calculations; π-π interactions