Molecular Basis of MC1R Activation: Mutation-Induced Alterations in Structural Dynamics.

IF 3.2 4区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Proteins-Structure Function and Bioinformatics Pub Date : 2024-11-01 Epub Date: 2024-06-25 DOI:10.1002/prot.26722

Fernando Guimarães Cavatão, Éderson Sales Moreira Pinto, Mathias J Krause, Clarice Sampaio Alho, Marcio Dorn

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引用次数: 0

Abstract

The MC1R protein is a receptor found in melanocytes that plays a role in melanin synthesis. Mutations in this protein can impact hair color, skin tone, tanning ability, and increase the risk of skin cancer. The MC1R protein is activated by the alpha-melanocyte-stimulating hormone (α-MSH). Previous studies have shown that mutations affect the interaction between MC1R and α-MSH; however, the mechanism behind this process is poorly understood. Our study aims to shed light on this mechanism using molecular dynamics (MD) simulations to analyze the Asp84Glu and Asp294His variants. We simulated both the wild-type (WT) protein and the mutants with and without ligand. Our results reveal that mutations induce unique conformations during state transitions, hindering the switch between active and inactive states and decreasing cellular levels of cAMP. Interestingly, Asp294His showed increased ligand affinity but decreased protein activity, highlighting that tighter binding does not always lead to increased activation. Our study provides insights into the molecular mechanisms underlying the impact of MC1R mutations on protein activity.

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MC1R 激活的分子基础：突变诱导的结构动力学变化。

MC1R 蛋白是一种存在于黑色素细胞中的受体，在黑色素合成过程中发挥作用。这种蛋白质的突变会影响头发颜色、肤色、晒黑能力，并增加患皮肤癌的风险。MC1R 蛋白由α-黑色素细胞刺激素（α-MSH）激活。以往的研究表明，突变会影响 MC1R 与 α-MSH 之间的相互作用；然而，人们对这一过程背后的机制还知之甚少。我们的研究旨在利用分子动力学（MD）模拟来分析 Asp84Glu 和 Asp294His 变体，从而揭示这一机制。我们模拟了野生型（WT）蛋白质以及含有或不含配体的突变体。我们的结果表明，突变体在状态转换过程中会诱发独特的构象，阻碍活性和非活性状态之间的切换，降低细胞中的 cAMP 水平。有趣的是，Asp294His 增加了配体亲和力，但降低了蛋白质活性，这说明更紧密的结合并不总是导致活化程度的提高。我们的研究深入揭示了MC1R突变对蛋白活性影响的分子机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Proteins-Structure Function and Bioinformatics 生物-生化与分子生物学

CiteScore

5.90

自引率

3.40%

发文量

172

审稿时长

3 months

期刊介绍： PROTEINS : Structure, Function, and Bioinformatics publishes original reports of significant experimental and analytic research in all areas of protein research: structure, function, computation, genetics, and design. The journal encourages reports that present new experimental or computational approaches for interpreting and understanding data from biophysical chemistry, structural studies of proteins and macromolecular assemblies, alterations of protein structure and function engineered through techniques of molecular biology and genetics, functional analyses under physiologic conditions, as well as the interactions of proteins with receptors, nucleic acids, or other specific ligands or substrates. Research in protein and peptide biochemistry directed toward synthesizing or characterizing molecules that simulate aspects of the activity of proteins, or that act as inhibitors of protein function, is also within the scope of PROTEINS. In addition to full-length reports, short communications (usually not more than 4 printed pages) and prediction reports are welcome. Reviews are typically by invitation; authors are encouraged to submit proposed topics for consideration.