Exploring the structural constraints at cleavage site of mucin 1 isoform through molecular dynamics simulation

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• 作者：J. Lesitha Jeeva Kumari ; C. Sudandiradoss
• 关键词：Peptide strain ; Autoproteolysis ; Molecular dynamics simulation ; Cleavage site ; Motif
• 刊名：European Biophysics Journal
• 出版年：2015
• 出版时间：July 2015
• 年：2015
• 卷：44
• 期：5
• 页码：309-323
• 全文大小：3,136 KB
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• 作者单位：J. Lesitha Jeeva Kumari (1)
  C. Sudandiradoss (1)
  
  1. Bioinformatics Division, School of Bioscience and Technology, VIT University, Vellore, 632 014, India
  
• 刊物类别：Physics and Astronomy
• 刊物主题：Physics
  Biophysics and Biomedical Physics
  Cell Biology
  Biochemistry
  Plant Physiology
  Animal Physiology
  Neurobiology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1017

文摘

In silico alanine scanning mutagenesis on the cleavable isoform of mucin 1 revealed isoleucine 67 as one of the key factors contributing to the strain at the autoproteolytic cleavage site. In this study, we demonstrate the structural basis of isoleucine-induced rigidity towards the strain-driven autoproteolysis at G?S+1 cleavage site of mucin 1. We further evaluated the gain in flexibility upon isoleucine 67 mutation through molecular dynamics and essential dynamics studies. The results show that the mutant exhibits stability in its secondary structural elements while the native displays a less-bonded network, however the cleavage site of native remains constrained. Essential dynamics revealed that large motions of the mutant were confined to the loop although the internal domain of the structure remains unaffected. Also, the mutation exerted a larger effect on the intraprotein interactions and consequently resulted in a stabilized motif at the cleavage. Analyses on MD trajectory conformations illustrate a completely disrupted motif in native as an effect of the peptide strain. The study also revealed that in mutant, the cleavage competent catalytic groups C=O and OG were in geometrical aspects unfavorable for a nucleophilic attack. The results support the earlier speculation that the presence of bulky isoleucine proximal G?S+1 cleavage site limits the conformational sampling of residues and therefore maintains the residues in a torsionally restrained conformation.