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AuthorS, Udhaya Kumar
AuthorSankar, Srivarshini
AuthorYounes, Salma
AuthorD, Thirumal Kumar
AuthorAhmad, Muneera Naseer
AuthorOkashah, Sarah Samer
AuthorKamaraj, Balu
AuthorAl-Subaie, Abeer Mohammed
AuthorC, George Priya Doss
AuthorZayed, Hatem
Available date2020-12-06T05:39:47Z
Publication Date2020-11-01
Publication NameMolecules
Identifierhttp://dx.doi.org/10.3390/molecules25235543
CitationS., 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.
URIhttp://hdl.handle.net/10576/17197
AbstractFilamins (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.
SponsorThis 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.
Languageen
PublisherMDPI
SubjectCH2 domain
FLNB
Larsen syndrome
atelosteogenesis type I
boomerang dysplasia
molecular dynamics simulation (MDS)
TitleDeciphering 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.
TypeArticle
Issue Number23
Volume Number25
ESSN1420-3049
dc.accessType Open Access


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