B cell lymphoma 2 (Bcl-2) residues essential for Bcl-2's apoptosis-inducing interaction with Nur77/Nor-1 orphan steroid receptors.
Apoptosis is mediated through the extrinsic or intrinsic pathway. Key regulators of the intrinsic apoptotic pathway are the family of B cell lymphoma 2 (Bcl-2) proteins. The activity of the prototypical Bcl-2 protein is usually considered antiapoptotic. However, under some conditions, Bcl-2 associates with the orphan nuclear hormone receptors Nur77 and Nor-1, converting Bcl-2 into a proapoptotic molecule. Expression of Nur77 and Nor-1 is induced by a variety of signals, including those leading to apoptosis. Translocation of Nur77/Nor-1 to mitochondria results in their association with Bcl-2, exposing the Bcl-2 homology (BH) 3 domain and causing apoptosis. However, the molecular details of this interaction are incompletely understood. Here, through extensive Bcl-2 mutagenesis and functional assays, we identified residues within Bcl-2 that are essential for its interaction with Nur77/Nor-1. Although an initial report has suggested that an unstructured loop region between the Bcl-2 BH4 and BH3 domains is required for Bcl-2's interaction with Nur77/Nor-1, we found that it is dispensable for this interaction. Instead, we found important interacting residues at the BH4 domain and crucial interacting residues between the BH1 and BH2 domains. Bcl-2 alanine mutants at this region could no longer interact with Nur77/Nor-1 and could not initiate Nur77/Bcl-2-mediated cell death. However, they still retained their anti-apoptotic capability in two different death assays. These results establish crucial residues in Bcl-2 required for Nur77/Nor-1-mediated apoptosis and point to potential new strategies for manipulating Bcl-2 function.
['Banta|Karl L|KL|', 'Wang|Xinyue|X|', 'Das|Phani|P|', 'Winoto|Astar|A|']
D019943:Amino Acid Substitution D000818:Animals D017209:Apoptosis D004268:DNA-Binding Proteins D057809:HEK293 Cells D006367:HeLa Cells D006801:Humans D051379:Mice D020125:Mutation, Missense D009419:Nerve Tissue Proteins D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 D000072417:Protein Domains D019253:Proto-Oncogene Proteins c-bcl-2 D011987:Receptors, Steroid D011988:Receptors, Thyroid Hormone
Nur77 Nor-1 apoptosis B-cell lymphoma 2 (Bcl-2) family Bcl-b apoptosis regulator mitochondrial apoptosis protein-protein interaction steroid hormone receptor