A mechanistic approach for islet amyloid polypeptide aggregation to develop anti-amyloidogenic agents for type-2 diabetes |
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Authors: | Ahmad Ejaz Ahmad Aqeel Singh Saurabh Arshad Md Khan Abdul Hameed Khan Rizwan Hasan |
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Institution: | a Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, India b Molecular and Structural Biology Division, Central Drug Research Institute, Lucknow 206001, India c Biophysical Chemistry Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi 110062, India d Molecular Endocrinology Laboratory, Department of Zoology, Lucknow University, Lucknow 206001, India e Centre for Population and Health Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G116NT, UK |
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Abstract: | Type-2 diabetes mellitus (DM-2) is a conformational disease involving intrinsically disordered islet amyloid polypeptide (IAPP), in which a structural transition from physiological polypeptide to pathological deposits takes place. Different factors acquired or inherited, contribute to endoplasmic reticulum stress and/or impair mitochondrial function which leads to conformational changes in IAPP intermediates and ultimately produces oligomers of an anti-parallel crossed β-pleated sheets that eventually accumulate as space-occupying lesions within the islets. Clusters of IAPP monomers form a pore which is linked to channel-like behavior in planar bilayers, indicating that these oligomeric IAPP pores could become incorporated into membranes and alter its barrier properties. Identification of nucleating residues and the residues responsible for this oligomeric tendency could improve understanding of structure-function relationships as well as the molecular mechanism of folding and aggregation of IAPP contributing to the onset of DM-2. A combination of biological, chemical or physical approaches is required to be extensively pursued for the development of a successful anti-amyloidogenic agent to prevent this malady. Exploring the hypothesis of π-stacking may be a better option to control IAPP aggregation if researchers go through the mechanism of π-π interaction, which provides entropy driven energy and direction for self-assembly to control amyloidogenic aggregation. |
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Keywords: | Amylin Amyloidogenesis Diabetes mellitus type-2 Intrinsically disordered polypeptide π-π stacking |
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