A multimeric model for murine anti-apoptotic protein Bcl-2 and structural insights for its regulation by post-translational modification

Venkatarajan S. Mathura, Kizhake V. Soman, Tushar K. Varma, Werner Braun

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

A monomeric model for murine antiapoptotic protein Bcl-2 was constructed by comparative modeling with the software suite MPACK (EXDIS/DIAMOD/FANTOM) using human Bcl-xL as a template. The monomeric model shows that murine Bcl-2 is an all α-helical protein with a central (helix 5) hydrophobic helix surrounded by amphipathic helices and an unstructured loop of 30 residues connecting helices 1 and 2. It has been previously shown that phosphorylation of Ser 70 located in this loop region regulates the anti-apoptotic activity of Bcl-2. Based on our current model, we propose that this phosphorylation may result in a conformational change that aids multimer formation. We constructed a model for the Bcl-2 homodimer based on the experimentally determined 3D structure of the Bcl-xL: Bad peptide complex. The model shows that it will require approximately a half turn in helix 2 to expose hydrophobic residues important for the formation of a multimer. Helices 5 and 6 of the monomeric subunit Bcl-2 have been proposed to form an ion-channel by associating with helices 5 and 6 of another monomeric subunit in the higher-order complex. In the multimeric model of Bcl-2, helices 5 and 6 of each subunit were placed distantly apart. From our model, we conclude that a global conformational change may be required to bring helices 5 and 6 together during ion-channel formation.

Original languageEnglish (US)
Pages (from-to)298-303
Number of pages6
JournalJournal of Molecular Modeling
Volume9
Issue number5
DOIs
StatePublished - 2003

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Keywords

  • Apoptosis
  • Distance geometry
  • Homology modeling

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics
  • Computer Science Applications
  • Computational Theory and Mathematics

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