Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis

Shamim Naghdi, Péter Várnai, György Hajnóczky

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Voltage-dependent anion channel (VDAC) proteins are major components of the outer mitochondrial membrane. VDAC has three isoforms with >70% sequence similarity and redundant roles in metabolite and ion transport. However, only Vdac2-/-(V2-/-) mice are embryonic lethal, indicating a unique and fundamental function of VDAC2 (V2). Recently, a specific V2 requirement was demonstrated for mitochondrial Bak import and truncated Bid (tBid)-induced apoptosis. To determine the relevant domain(s) of V2 involved, VDAC1 (V1) and V2 chimeric constructs were created and used to rescue V2-/- fibroblasts. Surprisingly, the commonly cited V2-specific N-terminal extension and cysteines were found to be dispensable for Bak import and high tBid sensitivity. In gain-offunction studies, V2 (123-179) was the minimal sequence sufficient to render V1 competent to support Bak insertion. Furthermore, in loss-of-function experiments, T168 and D170 were identified as critical residues. These motifs are conserved in zebrafish V2 (zfV2) that also rescued V2-deficient fibroblasts. Because high-resolution structures of zfV2 and mammalian V1 have become available, we could superimpose these structures and recognized that the critical V2-specific residues help to create a distinctive open "pocket" on the cytoplasmic surface that could facilitate Bak recruitment.

Original languageEnglish
Pages (from-to)E5590-E5599
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number41
DOIs
Publication statusPublished - Oct 13 2015

Keywords

  • Apoptosis
  • Bak
  • Mitochondria
  • VDAC2
  • tBid

ASJC Scopus subject areas

  • General

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