Crystal structures of Bax Reveal the Molecular Events that Initiate Programmed Cell Death — ASN Events
  1. Schedule
  2. Session Seven - Poster Session B includes Happy Hour & Trade Display
  3. Crystal structures of Bax Reveal the Molecular Events that Initiate Programmed Cell Death

Crystal structures of Bax Reveal the Molecular Events that Initiate Programmed Cell Death (#229)

Peter E Czabotar 1 2 , Dana Westphal 1 2 , Grant Dewson 1 2 , Stephen Ma 1 2 , Colin Hockings 1 2 , W Douglas Fairlie 1 2 , Erinna F Lee 1 2 , Shenggen Yao 1 2 , Adeline Y Robin 1 2 , Brian J Smith 3 , David C S Huang 1 2 , Ruth M Kluck 1 2 , Jerry M Adams 1 2 , Peter M Colman 1 2
  1. Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia
  3. La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, VIC, Australia

A key event in Programmed Cell Death is the conversion of Bax from an inert cytosolic monomer into a cytotoxic mitochondrial membrane perforating oligomer. Certain BH3-only relatives initiate this step through direct interactions, yet the means by which conformational changes are invoked, and the nature of the conformational changes themselves, has largely remained a mystery1. Here we present crystal structures of Bax in complex with BH3 domains, providing the first molecular details for these interactions. The structures, and subsequent mutagenesis studies, define the sequence signature of activator BH3 domains and reveal structural transitions required of Bax for death activity. A further structure for Bax helices α2-α5, a previously proposed minimal oligomerisation domain2, reveals a symmetric BH3-in-groove homodimer. This dimer, which is consistent with previous cross-linking studies3,4  and biophysical measurements5, is believed to be the unit on which the pore-forming oligomer is assembled. These structures provide the first structural insights into Bax activation. They additionally provide a novel rationale for targeting Bax with therapeutics, both agonists to induce cell death in diseases such as cancer, and antagonists to inhibit cell death in diseases such as degenerative disorders.

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  4. G. Dewson et al., Cell Death Differ, 19, 661, (2011).
  5. S. Bleicken et al., J Biol Chem 285, 6636 (2010).