Deciphering the Role of Filamin B Calponin-Homology Domain in Causing the Larsen Syndrome, Boomerang Dysplasia, and Atelosteogenesis Type I Spectrum Disorders via a Computational Approach.
المؤلف | S, Udhaya Kumar |
المؤلف | Sankar, Srivarshini |
المؤلف | Younes, Salma |
المؤلف | D, Thirumal Kumar |
المؤلف | Ahmad, Muneera Naseer |
المؤلف | Okashah, Sarah Samer |
المؤلف | Kamaraj, Balu |
المؤلف | Al-Subaie, Abeer Mohammed |
المؤلف | C, George Priya Doss |
المؤلف | Zayed, Hatem |
تاريخ الإتاحة | 2020-12-06T05:39:47Z |
تاريخ النشر | 2020-11-01 |
اسم المنشور | Molecules |
المعرّف | http://dx.doi.org/10.3390/molecules25235543 |
الاقتباس | S., U.K.; Sankar, S.; Younes, S.; D., T.K.; Ahmad, M.N.; Okashah, S.S.; Kamaraj, B.; Al-Subaie, A.M.; C., G.P.D.; Zayed, H. Deciphering the Role of Filamin B Calponin-Homology Domain in Causing the Larsen Syndrome, Boomerang Dysplasia, and Atelosteogenesis Type I Spectrum Disorders via a Computational Approach. Molecules 2020, 25, 5543. |
الملخص | 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 variants are Larsen syndrome, atelosteogenesis type I (AOI), atelosteogenesis type III (AOIII), and boomerang dysplasia (BD). Despite the intense clustering of 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. |
راعي المشروع | This publication was supported by Qatar University Internal Grant No QUST-2-CHS-2020-12. Udhaya Kumar. S, one of the authors, gratefully acknowledges the Indian Council of Medical Research (ICMR), India, for providing him a Senior Research Fellowship [ISRM/11(93)/2019]. The authors would like to thank the Vellore Institute of Technology, India, and Qatar University, Qatar, for providing the necessary research facilities and encouragement to carry out this work. |
اللغة | en |
الناشر | MDPI |
الموضوع | CH2 domain FLNB Larsen syndrome atelosteogenesis type I boomerang dysplasia molecular dynamics simulation (MDS) |
النوع | Article |
رقم العدد | 23 |
رقم المجلد | 25 |
ESSN | 1420-3049 |
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