Structural and Functional Analysis of Human SOD1 in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with familial inheritance (fALS) in 5% to 10% of cases; 25% of those are caused by mutations in the superoxide dismutase 1 (SOD1) protein. More than 100 mutations in the SOD1 gene have been associated with fALS, altering the geometry of the active site, protein folding and the interaction between monomers. We performed a functional analysis of non-synonymous single nucleotide polymorphisms (nsSNPs) in 124 fALS SOD1 mutants. Eleven different algorithms were used to estimate the functional impact of the replacement of one amino acid on protein structure: SNPs&GO, PolyPhen-2, SNAP, PMUT, Sift, PhD-SNP, nsSNPAnalyzer, TANGO, WALTZ, LIMBO and FoldX. For the structural analysis, theoretical models of 124 SNPs of SOD1 were created by comparative modeling using the MHOLline workflow, which includes Modeller and Procheck. Models were aligned with the native protein by the TM-align algorithm. A human-curated database was developed using the server side include in Java, JMOL. The results of this functional analysis indicate that the majority of the 124 natural mutants are harmful to the protein structure and thus corroborate the correlation between the reported mutations and fALS. In the structural analysis, all models showed conformational changes when compared to wild-type SOD1, and the degree of structural alignment varied between them. The SOD1 database converge structural and functional analyses of SOD1; it is a vast resource for the molecular analysis of amyotrophic lateral sclerosis, which allows the user to expand his knowledge on the molecular basis of the disease. The SOD1 database is available at http://bioinfogroup.com/database.肌萎缩侧索硬化症（Amyotrophic lateral sclerosis, ALS）是一种致命的神经退行性疾病，其中5%~10%的病例为家族性肌萎缩侧索硬化（familial ALS, fALS）；在家族性病例中，有25%由超氧化物歧化酶1（superoxide dismutase 1, SOD1）蛋白的突变所引发。目前已在SOD1基因中发现超过100种与fALS相关的突变，这些突变会改变活性位点的几何构象、蛋白质折叠方式以及单体间的相互作用。 本研究对124个fALS相关的SOD1突变体的非同义单核苷酸多态性（non-synonymous single nucleotide polymorphisms, nsSNPs）开展了功能分析。我们采用11种不同的算法评估单个氨基酸替换对蛋白质结构的功能影响，分别为SNPs&GO、PolyPhen-2、SNAP、PMUT、Sift、PhD-SNP、nsSNPAnalyzer、TANGO、WALTZ、LIMBO与FoldX。 在结构分析环节，我们借助包含Modeller与Procheck的MHOLline工作流，通过比较建模法构建了124个SOD1 SNPs的理论模型。随后使用TM-align算法将这些模型与天然蛋白质进行结构比对。 本研究采用Java服务端技术与JMOL工具开发了人工注释数据库。本项功能分析的结果显示，124个天然突变体中的绝大多数会对蛋白质结构造成损害，从而证实了已报道的突变与fALS之间的相关性。在结构分析中，所有模型与野生型SOD1相比均出现了构象变化，且不同模型间的结构比对程度存在差异。 该SOD1数据库整合了SOD1的结构与功能分析结果，是开展肌萎缩侧索硬化症分子研究的宝贵资源，可帮助用户深入理解该疾病的分子机制。该SOD1数据库的访问地址为http://bioinfogroup.com/database。