Biocomputing Group, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy.
Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), Italian National Research Council (CNR), 70126 Bari, Italy.
Int J Mol Sci. 2021 Dec 23;23(1):167. doi: 10.3390/ijms23010167.
MTHFR deficiency still deserves an investigation to associate the phenotype to protein structure variations. To this aim, considering the MTHFR wild type protein structure, with a catalytic and a regulatory domain and taking advantage of state-of-the-art computational tools, we explore the properties of 72 missense variations known to be disease associated. By computing the thermodynamic ΔΔG change according to a consensus method that we recently introduced, we find that 61% of the disease-related variations destabilize the protein, are present both in the catalytic and regulatory domain and correspond to known biochemical deficiencies. The propensity of solvent accessible residues to be involved in protein-protein interaction sites indicates that most of the interacting residues are located in the regulatory domain, and that only three of them, located at the interface of the functional protein homodimer, are both disease-related and destabilizing. Finally, we compute the protein architecture with Hidden Markov Models, one from Pfam for the catalytic domain and the second computed in house for the regulatory domain. We show that patterns of disease-associated, physicochemical variation types, both in the catalytic and regulatory domains, are unique for the MTHFR deficiency when mapped into the protein architecture.
MTHFR 缺陷仍然值得研究，以将表型与蛋白质结构变异联系起来。为此，考虑到 MTHFR 野生型蛋白质结构，具有催化和调节结构域，并利用最先进的计算工具，我们探索了已知与疾病相关的 72 种错义变异的性质。通过根据我们最近引入的共识方法计算热力学 ΔΔG 变化，我们发现 61%的与疾病相关的变异会使蛋白质不稳定，存在于催化和调节结构域中，并对应于已知的生化缺陷。溶剂可及残基参与蛋白质-蛋白质相互作用位点的倾向表明，大多数相互作用残基位于调节结构域，而只有三个位于功能蛋白同源二聚体界面的残基，既是疾病相关的，也是不稳定的。最后，我们使用隐马尔可夫模型计算蛋白质结构，一个来自 Pfam 的催化结构域，另一个在内部计算的调节结构域。我们表明，当映射到蛋白质结构时，与疾病相关的、物理化学变异类型的模式在 MTHFR 缺陷中是独特的，无论是在催化结构域还是调节结构域中。
