Mechanistic insight into functionally different human islet polypeptide (hIAPP) amyloid: the intrinsic role of the C-terminal structural motifs.
Mechanistic insight into functionally different human islet polypeptide (hIAPP) amyloid: the intrinsic role of the C-terminal structural motifs.
复制标题
对功能不同的人胰岛多肽 (hIAPP) 淀粉样蛋白的机制洞察：C 端结构基序的内在作用。
DOI：
10.1039/d2cp01650h
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Bhunia,Anirban
中科院分区：
文献类型：
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作者：
Sarkar,Dibakar;Maity,NarayanChandra;Shome,Gourav;Varnava,KyriakosGabriel;Sarojini,Vijayalekshmi;Vivekanandan,Subramanian;Sahoo,Nirakar;Kumar,Sourav;Mandal,AtinKumar;Biswas,Ranjit;Bhunia,Anirban
以淀粉样变性为靶点需要对淀粉样蛋白聚集的潜在机制有高分辨率的了解。多肽或蛋白质的序列特有的固有性质在很大程度上决定了淀粉样变性的倾向。因此，有必要勾勒出定义后续下游淀粉样蛋白致病级联事件的结构基序。此外，重要的是要了解外部因素，如温度或样品搅拌，在调节促使不同成核事件的总能垒方面所起的作用。因此，这些变化可以影响纤颤动力学，导致与疾病发病机制相关的结构和功能上不同的淀粉样变性构象。在这里，我们重点研究了在不同温度和样品搅拌条件下，全长多肽及其N-末端和C-末端片段的人胰岛多肽(HIAPP)淀粉样蛋白的发生。这有助于我们全面了解特定功能表位在调节淀粉样蛋白发生和随后的细胞毒性的多肽一级结构中的内在作用。有趣的是，我们的研究涉及一系列生物物理实验和体外数据，表明外部变化对C末端纤颤序列有直接影响。此外，观察表明，该片段在生理场景中可能在核化hIAPP淀粉样蛋白发生中发挥协同作用，从而使其成为未来治疗干预的潜在靶点。
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.