In silico functional and structural characterisation of ferlin proteins by mapping disease-causing mutations and evolutionary information onto three-dimensional models of their C2 domains
In silico functional and structural characterisation of ferlin proteins by mapping disease-causing mutations and evolutionary information onto three-dimensional models of their C2 domains
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DOI：
10.1016/j.jns.2007.04.016
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发表时间：
2007-09-15
影响因子：
4.4
通讯作者：
Bashir, Rumaisa
中科院分区：
文献类型：
--
作者：
Jimenez, Jose L.;Bashir, Rumaisa
Ferlin是参与膜融合事件（包括膜修复和突触胞吐）的C2结构域蛋白，并且其缺乏可导致肌营养不良和耳聋。我们通过序列比较和同源性建模对其C2结构域进行了结构研究，以了解这些特征不明显的蛋白质的功能，并预测致病突变的分子影响。我们观察到，非保守突变影响掩埋残基往往会导致有害的表型，可能是因为降低蛋白质的稳定性，而大多数变体与表面残基的替代没有。已知引起疾病的变体中暴露残基改变的少数情况发现于具有重要功能的保守区域，包括必需的钙结合区，如通过类比其他特征C2结构域所推断的。此外，我们报告了两个已知的ferlin亚家族中的一些C2结构域的不同特征，这些特征与DysF结构域的存在或不存在相关。总之，我们的研究结果突出了进一步实验分析的潜在目标，以了解ferlin蛋白的功能。我们相信，我们的建模数据将有助于诊断与ferlin突变相关的疾病和开发治疗策略。(C)2007 Elsevier B.V.保留所有权利。
Ferlins are C2 domain proteins involved in membrane fusion events, including membrane repair and synaptic exocytosis, and their deficiency can result in muscular dystrophy and deafness. We have undertaken a structural study of their C2 domains by sequence comparison and homology modelling to understand the function of these poorly characterised proteins and to predict the molecular impact of disease-causing mutations. We observe that non-conservative mutations affecting buried residues tend to result in detrimental phenotypes, likely because of decreased protein stability, whereas most variants with replacements in surface residues do not. The few cases of exposed residues altered in variants known to cause diseases are found in conserved areas of functional importance, including essential calcium-binding regions, as deduced by analogy to other characterised C2 domains. Furthermore, we report distinct features of some C2 domains in the two known ferlin subfamilies that correlates with the presence or absence of the DysF domains. Taken altogether, our results highlight potential targets for further experimental analyses to understand the function of ferlin proteins. We believe our modelling data will aid the diagnosis of diseases associated with ferlin mutations and the development of therapeutic strategies. (C) 2007 Elsevier B.V. All rights reserved.