title: Mutation-Structure-Function Relationship Based Integrated Strategy Reveals the Potential Impact of Deleterious Missense Mutations in Autophagy Related Proteins on Hepatocellular Carcinoma (HCC): A Comprehensive Informatics Approach.
abstract: Autophagy, an evolutionary conserved multifaceted lysosome-mediated bulk degradation system, plays a vital role in liver pathologies including hepatocellular carcinoma (HCC). Post-translational modifications (PTMs) and genetic variations in autophagy components have emerged as significant determinants of autophagy related proteins. Identification of a comprehensive spectrum of genetic variations and PTMs of autophagy related proteins and their impact at molecular level will greatly expand our understanding of autophagy based regulation. In this study, we attempted to identify high risk missense mutations that are highly damaging to the structure as well as function of autophagy related proteins including LC3A, LC3B, BECN1 and SCD1. Number of putative structural and functional residues, including several sites that undergo PTMs were also identified. In total, 16 high-risk SNPs in LC3A, 18 in LC3B, 40 in BECN1 and 43 in SCD1 were prioritized. Out of these, 2 in LC3A (K49A, K51A), 1 in LC3B (S92C), 6 in BECN1 (S113R, R292C, R292H, Y338C, S346Y, Y352H) and 6 in SCD1 (Y41C, Y55D, R131W, R135Q, R135W, Y151C) coincide with potential PTM sites. Our integrated analysis found LC3B Y113C, BECN1 I403T, SCD1 R126S and SCD1 Y218C as highly deleterious HCC-associated mutations. This study is the first extensive in silico mutational analysis of the LC3A, LC3B, BECN1 and SCD1 proteins. We hope that the observed results will be a valuable resource for in-depth mechanistic insight into future investigations of pathological missense SNPs using an integrated computational platform.
authors.affiliation: Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad 44000, Pakistan. faryal_mehwish@yahoo.com.
authors.forename: Faryal Mehwish
authors.initials: FM
authors.lastname: Awan
authors.affiliation: Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad 44000, Pakistan. ayesha_obaid_nust@live.com.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Obaid
authors.affiliation: Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad 44000, Pakistan. aqsa_ikram@yahoo.com.
authors.forename: Aqsa
authors.initials: A
authors.lastname: Ikram
authors.affiliation: Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad 44000, Pakistan. janjua.hussnain@gmail.com.
authors.forename: Hussnain Ahmed
authors.initials: HA
authors.lastname: Janjua
mesh_terms: D000595:Amino Acid Sequence; D000071183:Autophagy-Related Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism*; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D017124:Conserved Sequence; D030541:Databases, Genetic; D066264:Datasets as Topic; D019143:Evolution, Molecular; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D020125:Mutation, Missense; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000071183:Autophagy-Related Proteins
keywords: autophagy related proteins; computational analysis; hepatocellular carcinoma; missense single nucleotide polymorphisms; post-translational modifications