Open AccessAmyloidogenicity and cytotoxicity of des-Lys-1 human amylin provides insight into amylin self-assembly and highlights the difficulties of defining amyloidogenicity
Author(s) -
Kyung-Hoon Lee,
Alexander Zhyvoloup,
Daniel P. Raleigh
Publication year - 2019
Publication title -
protein engineering, design and selection
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.627
H-Index - 109
eISSN - 1741-0134
pISSN - 1741-0126
DOI - 10.1093/protein/gzz036
Subject(s) - amylin , amyloid (mycology) , islet , chemistry , in vitro , biochemistry , peptide , cytotoxicity , insulin , biology , endocrinology , inorganic chemistry
The polypeptide amylin is responsible for islet amyloid in type 2 diabetes, a process which contributes to β-cell death in the disease. The role of the N-terminal region of amylin in amyloid formation is relatively unexplored, although removal of the disulfide bridged loop between Cys-2 and Cys-7 accelerates amyloid formation. We examine the des Lys-1 variant of human amylin (h-amylin), a variant which is likely produced in vivo. Lys-1 is a region of high charge density in the h-amylin amyloid fiber. The des Lys-1 polypeptide forms amyloid on the same time scale as wild-type amylin in phosphate buffered saline, but does so more rapidly in Tris. The des Lys-1 variant is somewhat less toxic to cultured INS cells than wild type. The implications for the in vitro mechanism of amyloid formation and for comparative analysis of amyloidogenicity are discussed.