title: How the imidazole ring modulates amyloid formation of islet amyloid polypeptide: A chemical modification study.
abstract: BACKGROUND
  The misfolding of human islet amyloid polypeptide (hIAPP) is an important pathological factor on the onset of type 2 diabetes. A number of studies have been focused on His(18), the only histidine of hIAPP, whose imidazole ring and the protonation state might impact hIAPP amyloid formation, but the exact mechanism remains unclear.
  
  
  METHODS
  We used diethylpyrocarbonate (DEPC) to specifically modify His(18) and obtained mono-ethyloxyformylated hIAPP (DMI). Thioflavin T based fluorescence, transmission electronic microscopy, circular dichroism spectroscopy, fluorescence dye leakage, Fourier transform infrared spectroscopy and replica-exchange molecular dynamics (REMD) simulation were applied to study the impact of DEPC-modification on hIAPP amyloid formation.
  
  
  RESULTS
  After an ethyl-acetate group was introduced to the His(18) of hIAPP by diethylpyrocarbonate (DEPC) modification, the pH dependent hIAPP fibrillation went to the opposite order and the number of intra-molecular hydrogen bonds decreased, while the possibility of His(18) participating in the formation of α-helical structures increased. Furthermore, the membrane-peptide interaction and ion-peptide interaction were both impaired.
  
  
  CONCLUSIONS
  The intramolecular hydrogen bond formation by His(18) and the possibility of His(18) participating in the formation of α-helical structures greatly modulated the manner of hIAPP amyloid formation. The imidazole ring directly participates in the hIAPP-membrane/ion interaction.
  
  
  CONCLUSIONS
  DEPC modification is an alternative approach to investigate the role of the imidazole ring during amyloid formation.
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Junjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Lianqi
authors.initials: L
authors.lastname: Huang
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, 44106, OH, USA; Department of Neuroscience, Case Western Reserve University, Cleveland, 44106, OH, USA; Department of Neurology, Case Western Reserve University, Cleveland, 44106, OH, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Petersen
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Gong
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: lzheng217@hotmail.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science & Technology, Wuhan 430030, China. Electronic address: kunhuang2008@hotmail.com.
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
mesh_terms: D052160:Benzothiazoles; D004047:Diethyl Pyrocarbonate / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D046912:Multiprotein Complexes / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D052160:Benzothiazoles; D007093:Imidazoles; D058228:Islet Amyloid Polypeptide; D046912:Multiprotein Complexes; D013844:Thiazoles; C009462:thioflavin T; C029899:imidazole; D004047:Diethyl Pyrocarbonate
keywords: Amyloid; Imidazole ring; Modification; hIAPP