Mechanistic insight into functionally different human islet polypeptide (hIAPP) amyloid: the intrinsic role of the C-terminal structural motifs

Authors

Dibakar Sarkar
Narayan Chandra Maity
Gourav Shome
Kyriakos Gabriel Varnava
Vijayalekshmi Sarojini
Subramanian Vivekanandan
Nirakar Sahoo, The University of Texas Rio Grande ValleyFollow
Sourav Kumar
Atin Kumar Mandal
Ranjit Biswas
Anirban Bhunia

Document Type

Article

Publication Date

9-21-2022

Abstract

Targeting amyloidosis requires high-resolution insight into the underlying mechanisms of amyloid aggregation. The sequence-specific intrinsic properties of a peptide or protein largely govern the amyloidogenic propensity. Thus, it is essential to delineate the structural motifs that define the subsequent downstream amyloidogenic cascade of events. Additionally, it is important to understand the role played by extrinsic factors, such as temperature or sample agitation, in modulating the overall energy barrier that prompts divergent nucleation events. Consequently, these changes can affect the fibrillation kinetics, resulting in structurally and functionally distinct amyloidogenic conformers associated with disease pathogenesis. Here, we have focused on human Islet Polypeptide (hIAPP) amyloidogenesis for the full-length peptide along with its N- and C-terminal fragments, under different temperatures and sample agitation conditions. This helped us to gain a comprehensive understanding of the intrinsic role of specific functional epitopes in the primary structure of the peptide that regulates amyloidogenesis and subsequent cytotoxicity. Intriguingly, our study involving an array of biophysical experiments and ex vivo data suggests a direct influence of external changes on the C-terminal fibrillating sequence. Furthermore, the observations indicate a possible collaborative role of this segment in nucleating hIAPP amyloidogenesis in a physiological scenario, thus making it a potential target for future therapeutic interventions.

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Recommended Citation

Sarkar, D., Maity, N. C., Shome, G., Varnava, K. G., Sarojini, V., Vivekanandan, S., Sahoo, N., Kumar, S., Mandal, A. K., Biswas, R., & Bhunia, A. (2022). Mechanistic insight into functionally different human islet polypeptide (hIAPP) amyloid: the intrinsic role of the C-terminal structural motifs. Physical chemistry chemical physics : PCCP, 24(36), 22250–22262. https://doi.org/10.1039/d2cp01650h

Publication Title

Phys Chem Chem Phys

DOI

10.1039/d2cp01650h