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Abstract：
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.
摘要：
MTHFR缺乏仍然值得研究以将表型与蛋白质结构变异相关联。为了这个目标,考虑到MTHFR野生型蛋白结构，具有催化和调节域，并利用最先进的计算工具，我们探索了72种已知与疾病相关的错义变异的性质。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%的疾病相关变异会破坏蛋白质的稳定性，存在于催化和调节域中，并且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域，只有三个，位于功能蛋白同二聚体的界面，既与疾病相关又破坏稳定。最后,我们用隐马尔可夫模型计算蛋白质结构，一个来自Pfam的催化域，第二个是内部计算的调节域。我们表明疾病相关的模式，物理化学变异类型，在催化和调控领域，当映射到蛋白质结构中时，对于MTHFR缺乏是独一无二的。
