Prioritization of SNPs in y+LAT-1 culpable of Lysinuric protein intolerance and their mutational impacts using protein-protein docking and molecular dynamics simulation studies

Chandrasekhar Gopalakrishnan, Abeer Mohammed Al-Subaie, N. Nagasundaram, Hui Yuan Yeh, Iftikhar Alam Tayubi, Balu Kamaraj

Research output: Contribution to journalJournal articlepeer-review

6 Scopus citations

Abstract

Lysinuric protein intolerance (LPI) is a rare, yet inimical, genetic disorder characterized by the paucity of essential dibasic amino acids in the cells. Amino acid transporter y+LAT-1 interacts with 4F2 cell-surface antigen heavy chain to transport the required dibasic amino acids. Mutation in y+LAT-1 is rumored to cause LPI. However, the underlying pathological mechanism is unknown, and, in this analysis, we investigate the impact of point mutation in y+LAT-1's interaction with 4F2 cell-surface antigen heavy chain in causing LPI. Using an efficient and extensive computational pipeline, we have isolated M50K and L334R single-nucleotide polymorphisms to be the most deleterious mutations in y+LAT-1s. Docking of mutant y+LAT-1 with 4F2 cell-surface antigen heavy chain showed decreased interaction compared with native y+LAT-1. Further, molecular dynamic simulation analysis reveals that the protein molecules increase in size, become more flexible, and alter their secondary structure upon mutation. We believe that these conformational changes because of mutation could be the reason for decreased interaction with 4F2 cell-surface antigen heavy chain causing LPI. Our analysis gives pathological insights about LPI and helps researchers to better understand the disease mechanism and develop an effective treatment strategy.

Original languageEnglish
Pages (from-to)18496-18508
Number of pages13
JournalJournal of Cellular Biochemistry
Volume120
Issue number10
DOIs
StatePublished - Oct 2019

Keywords

  • docking
  • loss of interaction
  • loss of stability
  • molecular dynamic simulation
  • single nucleotide polymorphism analysis

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