title: Computational Modeling of complete HOXB13 protein for predicting the functional effect of SNPs and the associated role in hereditary prostate cancer.
abstract: The human HOXB13 gene encodes a 284 amino acid transcription factor belonging to the homeobox gene family containing a homeobox and a HoxA13 N-terminal domain. It is highly linked to hereditary prostate cancer, the majority of which is manifested as a result of a Single Nucleotide Polymorphism (SNP). In silico analysis of 95 missense SNP's corresponding to the non-homeobox region of HOXB13 predicted 21 nsSNP's to be potentially deleterious. Among 123 UTR SNPs analysed by UTRScan, rs543028086, rs550968159, rs563065128 were found to affect the UNR_BS, GY-BOX and MBE UTR signals, respectively. Subsequent analysis by PolymiRTS revealed 23 UTR SNPs altering the miRNA binding site. The complete HOXB13_M26 protein structure was modelled using MODELLER v9.17. Computational analysis of the 21 nsSNP's mapped into the HOXB13_M26 protein revealed seven nsSNP's (rs761914407, rs8556, rs138213197, rs772962401, rs778843798, rs770620686 and rs587780165) seriously resulting in a damaging and deleterious effect on the protein. G84E, G135E, and A128V resulted in increased, while, R215C, C66R, Y80C and S122R resulted in decreased protein stability, ultimately predicted to result in the altered binding patterns of HOXB13. While the genotype-phenotype based effects of nsSNP's were assessed, the exact biological and biochemical mechanism driven by the above predicted SNPs still needs to be extensively evaluated by in vivo and GWAS studies.
authors.affiliation: Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Gopalakrishnan
authors.initials: G
authors.lastname: Chandrasekaran
authors.affiliation: Department of Urology, Chonnam National University Hospital, Gwangju, Republic of Korea.
authors.forename: Eu Chang
authors.initials: EC
authors.lastname: Hwang
authors.affiliation: Department of Urology, Chonnam National University Hospital, Gwangju, Republic of Korea.
authors.forename: Taek Won
authors.initials: TW
authors.lastname: Kang
authors.affiliation: Department of Urology, Chonnam National University Hospital, Gwangju, Republic of Korea.
authors.forename: Dong Deuk
authors.initials: DD
authors.lastname: Kwon
authors.affiliation: Department of Urology, Chonnam National University Hospital, Gwangju, Republic of Korea.
authors.forename: Kwangsung
authors.initials: K
authors.lastname: Park
authors.affiliation: Research Center for Cancer Immunotherapy, Chonnam National University Hospital, Gwangju, Republic of Korea.
authors.forename: Je-Jung
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Vinoth-Kumar
authors.initials: VK
authors.lastname: Lakshmanan
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D000072417:Protein Domains; D055550:Protein Stability
chemical_list: C484414:HOXB13 protein, human; D018398:Homeodomain Proteins