title: Human Islet Amyloid Polypeptide Assembly: The Key Role of the 8-20 Fragment.
abstract: The aggregation of human islet amyloid polypeptide (hIAPP) has been closely associated with the pathogeny of type 2 diabetes mellitus (T2DM) and destruction of pancreatic islet β-cells. Several amyloidogenic domains within the hIAPP sequence capable of self-association have been identified. Among them is the 8-20 region of hIAPP, which has formed β-sheet fibrils despite being contained within an α-helical region of full-length hIAPP. To further understand the propensity of this region for self-assembly, two peptide fragments were compared, one consisting of the residues 8-20 (WT8-20) and a mutant fragment with a His18Pro substitution (H18P8-20). The conformational distribution and aggregation propensity of these peptides was determined using a combination of ion mobility mass spectrometry and atomic force microscopy. Our results reveal that the two peptide fragments have vastly differing assembly pathways. WT8-20produces a wide range of oligomers up to decamer whereas the H18P8-20mutant produces only low order oligomers. This study confirms the propensity of the 8-20 region to aggregate from its native α-helical structure into amyloid β-sheet oligomers and highlights the significance of the charged His18 in the aggregation process.
authors: Department of Chemistry and Biochemistry, University of California , Santa Barbara, California 93106, United States.|State Key Laboratory of Supramolecular Structure and Materials, Jilin University , Changchun 130012, P. R. China.
authors: Li
authors: L
authors: Wang
authors: Department of Chemistry and Biochemistry, University of California , Santa Barbara, California 93106, United States.
authors: Alexandre I
authors: AI
authors: Ilitchev
authors: Department of Chemistry and Biochemistry, University of California , Santa Barbara, California 93106, United States.
authors: Maxwell J
authors: MJ
authors: Giammona
authors: State Key Laboratory of Supramolecular Structure and Materials, Jilin University , Changchun 130012, P. R. China.
authors: Fei
authors: F
authors: Li
authors: Department of Chemistry and Biochemistry, University of California , Santa Barbara, California 93106, United States.
authors: Steven K
authors: SK
authors: Buratto
authors: Department of Chemistry and Biochemistry, University of California , Santa Barbara, California 93106, United States.
authors: Michael T
authors: MT
authors: Bowers
mesh_terms: D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000138:chemical synthesis* / Q000737:chemistry / Q000235:genetics; D013058:Mass Spectrometry; D018625:Microscopy, Atomic Force; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics
chemical_list: D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments