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首页> 外文期刊>Biochemistry >Characterization of Amyloid Formation by Glucagon-Like Peptides: Role of Basic Residues in Heparin-Mediated Aggregation
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Characterization of Amyloid Formation by Glucagon-Like Peptides: Role of Basic Residues in Heparin-Mediated Aggregation

机译：胰高血糖素样肽形成淀粉样蛋白的表征：碱性残基在肝素介导的聚集中的作用。

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Glycosaminoglycans (GAGs) have been reported to play a significant role in amyloid formation of a wide range of proteins/peptides either associated with diseases or native biological functions. The exact mechanism by which GAGs influence amyloid formation is not clearly understood. Here, we studied two closely related peptides, glucagon-like peptide 1 (GLP1) and glucagon-like peptide 2 (GLP2), for their amyloid formation in the presence and absence of the representative GAG heparin using various biophysical and computational approaches. We show that the aggregation and amyloid formation by these peptides follow distinct mechanisms: GLP1 follows nucleation-dependent aggregation, whereas GLP2 forms amyloids without any significant lag time. Investigating the role of heparin, we also found that heparin interacts with GLP1, accelerates its aggregation, and gets incorporated within its amyloid fibrils. In contrast, heparin neither affects the aggregation kinetics of GLP2 nor gets embedded within its fibrils. Furthermore, we found that heparin preferentially influences the stability of the GLP1 fibrils over GLP2 fibrils. To understand the specific nature of the interaction of heparin with GLP1 and GLP2, we performed all-atom MD simulations. Our in silico results show that the basic-nonbasic-basic (B-X-B) motif of GLP1 (K28-G29- R30) facilitates the interaction between heparin and peptide monomers. However, the absence of such a motif in GLP2 could be the reason for a significantly lower strength of interaction between GLP2 and heparin. Our study not only helps to understand the role of heparin in inducing protein aggregation but also provides insight into the nature of heparin?protein interaction.
机译：据报道，糖胺聚糖（GAG）在与疾病或天然生物学功能有关的各种蛋白质/肽的淀粉样蛋白形成中起重要作用。 GAG影响淀粉样蛋白形成的确切机制尚不清楚。在这里，我们使用各种生物物理和计算方法研究了两种紧密相关的肽，即胰高血糖素样肽1（GLP1）和胰高血糖素样肽2（GLP2）在存在和不存在代表性GAG肝素的情况下它们的淀粉样蛋白形成。我们表明这些肽的聚集和淀粉样蛋白形成遵循不同的机制：GLP1遵循成核依赖性聚集，而GLP2形成淀粉样蛋白没有任何明显的滞后时间。在研究肝素的作用时，我们还发现肝素与GLP1相互作用，加速其聚集，并掺入其淀粉样蛋白原纤维中。相反，肝素既不影响GLP2的聚集动力学，也不嵌入其原纤维中。此外，我们发现肝素相对于GLP2原纤维优先影响GLP1原纤维的稳定性。为了了解肝素与GLP1和GLP2相互作用的特殊性质，我们进行了全原子MD模拟。我们的计算机模拟结果表明，GLP1（K28-G29-R30）的碱性-非碱性-碱性（B-X-B）图案促进了肝素与肽单体之间的相互作用。但是，GLP2中不存在此类基序可能是GLP2与肝素之间相互作用强度显着降低的原因。我们的研究不仅有助于了解肝素在诱导蛋白质聚集中的作用，而且还可以洞悉肝素与蛋白质相互作用的性质。

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