This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Bak is a member of the executioner-faction of the Bcl-2 protein family. Its function is normally antagonised by the Bcl-2 homologue Mcl-1, and Mcl-1 function is itself antagonised by the so-called BH3-only proteins that transmit various stress stimuli to the apoptotic machinery. Cells undergo apoptosis after receiving suitable stimuli such as e.g. DNA damage. This results in release of BH3-only proteins which, directly or indirectly, activate Bak (and Bax). Following release of BH3-only proteins, Bak and Bax undergo a structural transition (and probably oligomerization), and subsequently induce mitochondrial membrane permeabilisation (MMP). MMP represents the point of no return for a cell on the apoptosis pathway, and is of critical importance for subsequent cell death. Crystals of Mcl-1 with cognate BH3 peptide ligands diffract X-rays on a laboratory source to 2.0 A, but have proven refractory to molecular replacement. We wish to perform a MAD experiment on crystals of seleno-methionine incorporated Mcl-1 complexed with BH3 peptide
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