Filamins (FLN) are a family of actin-binding proteins involved in regulating the cytoskeleton and signaling phenomenon by developing a network with F-actin and FLN-binding partners. The FLN family comprises three conserved isoforms in mammals: FLNA, FLNB, and FLNC. FLNB is a multidomain monomer protein with domains containing an actin-binding N-terminal domain (ABD 1–242), encompassing two calponin-homology domains (assigned CH1 and CH2). Primary variants in FLNB mostly occur in the domain (CH2) and surrounding the hinge-1 region. The four autosomal dominant disorders that are associated with FLNB variants are Larsen syndrome, atelosteogenesis type I (AOI), atelosteogenesis type III (AOIII), and boomerang dysplasia (BD). Despite the intense clustering of FLNB variants contributing to the LS-AO-BD disorders, the genotype-phenotype correlation is still enigmatic. In silico prediction tools and molecular dynamics simulation (MDS) approaches have offered the potential for variant classification and pathogenicity predictions. We retrieved 285 FLNB missense variants from the UniProt, ClinVar, and HGMD databases in the current study. Of these, five and 39 variants were located in the CH1 and CH2 domains, respectively. These variants were subjected to various pathogenicity and stability prediction tools, evolutionary and conservation analyses, and biophysical and physicochemical properties analyses. Molecular dynamics simulation (MDS) was performed on the three candidate variants in the CH2 domain (W148R, F161C, and L171R) that were predicted to be the most pathogenic. The MDS analysis results showed that these three variants are highly compact compared to the native protein, suggesting that they could affect the protein on the structural and functional levels. The computational approach demonstrates the differences between the FLNB mutants and the wild type in a structural and functional context. Our findings expand our knowledge on the genotype-phenotype correlation in FLNB-related LS-AO-BD disorders on the molecular level, which may pave the way for optimizing drug therapy by integrating precision medicine.

中文翻译：

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通过计算方法破译细丝蛋白 B 钙调蛋白同源结构域在导致拉森综合征、飞去来器发育不良和 I 型骨质增生谱系疾病中的作用


细丝蛋白 (FLN) 是肌动蛋白结合蛋白家族，通过与 F-肌动蛋白和 FLN 结合伙伴形成网络，参与调节细胞骨架和信号传导现象。 FLN 家族包含哺乳动物中的三种保守亚型：FLNA、FLNB 和 FLNC。 FLNB 是一种多结构域单体蛋白，其结构域包含肌动蛋白结合 N 末端结构域 (ABD 1-242)，包含两个钙调蛋白同源结构域（指定为 CH1 和 CH2）。 FLNB 的主要变异主要发生在结构域 (CH2) 和铰链 1 区域周围。与 FLNB 变异相关的四种常染色体显性遗传疾病是 Larsen 综合征、I 型端骨形成 (AOI)、III 型端骨形成 (AOIII) 和飞去来器发育不良 (BD)。尽管 FLNB 变异的强烈聚集导致了 LS-AO-BD 疾病，但基因型-表型相关性仍然是个谜。计算机预测工具和分子动力学模拟（MDS）方法为变异分类和致病性预测提供了潜力。在本研究中，我们从 UniProt、ClinVar 和 HGMD 数据库中检索了 285 个 FLNB 错义变异。其中，5 个和 39 个变体分别位于 CH1 和 CH2 结构域。这些变体接受了各种致病性和稳定性预测工具、进化和保护分析以及生物物理和理化特性分析。对 CH2 结构域中的三个候选变体（W148R、F161C 和 L171R）进行了分子动力学模拟 (MDS)，这些变体被预测为最具致病性。 MDS分析结果表明，与天然蛋白相比，这三种变体高度紧凑，表明它们可以在结构和功能水平上影响蛋白。 计算方法证明了 FLNB 突变体和野生型在结构和功能方面的差异。我们的研究结果在分子水平上扩展了我们对 FLNB 相关 LS-AO-BD 疾病基因型-表型相关性的认识，这可能为通过整合精准医学来优化药物治疗铺平道路。