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المؤلفS, Udhaya Kumar
المؤلفSankar, Srivarshini
المؤلفYounes, Salma
المؤلفD, Thirumal Kumar
المؤلفAhmad, Muneera Naseer
المؤلفOkashah, Sarah Samer
المؤلفKamaraj, Balu
المؤلفAl-Subaie, Abeer Mohammed
المؤلفC, George Priya Doss
المؤلفZayed, Hatem
تاريخ الإتاحة2020-12-06T05:39:47Z
تاريخ النشر2020-11-01
اسم المنشورMolecules
المعرّفhttp://dx.doi.org/10.3390/molecules25235543
الاقتباسS., 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.
معرّف المصادر الموحدhttp://hdl.handle.net/10576/17197
الملخصFilamins (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 المشروعThis 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.
اللغةen
الناشرMDPI
الموضوعCH2 domain
FLNB
Larsen syndrome
atelosteogenesis type I
boomerang dysplasia
molecular dynamics simulation (MDS)
العنوانDeciphering 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.
النوعArticle
رقم العدد23
رقم المجلد25
ESSN1420-3049
dc.accessType Open Access


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