4CIM
Complex of a Bcl-w BH3 mutant with a BH3 domain
Summary for 4CIM
| Entry DOI | 10.2210/pdb4cim/pdb |
| Related | 4CIN |
| Descriptor | BCL-2-LIKE PROTEIN 2, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | apoptosis, cell death |
| Biological source | HOMO SAPIENS (HUMAN) More |
| Cellular location | Mitochondrion membrane ; Peripheral membrane protein : Q92843 Q92843 |
| Total number of polymer chains | 4 |
| Total formula weight | 41269.99 |
| Authors | Colman, P.M.,Lee, E.F.,Fairlie, W.D. (deposition date: 2013-12-12, release date: 2014-11-12, Last modification date: 2023-12-20) |
| Primary citation | Lee, E.F.,Dewson, G.,Evangelista, M.,Pettikiriarachchi, A.,Zhu, H.,Colman, P.M.,Fairlie, W.D. The Functional Differences of Pro-Survival and Pro-Apoptotic B Cell Lymphoma 2 (Bcl-2) Proteins Depend on Structural Differences in Their Bcl-2 Homology 3 (Bh3) Domains J.Biol.Chem., 289:36001-, 2014 Cited by PubMed Abstract: Bcl-2 homology 3 (BH3) domains are short sequence motifs that mediate nearly all protein-protein interactions between B cell lymphoma 2 (Bcl-2) family proteins in the intrinsic apoptotic cell death pathway. These sequences are found on both pro-survival and pro-apoptotic members, although their primary function is believed to be associated with induction of cell death. Here, we identify critical features of the BH3 domains of pro-survival proteins that distinguish them functionally from their pro-apoptotic counterparts. Biochemical and x-ray crystallographic studies demonstrate that these differences reduce the capacity of most pro-survival proteins to form high affinity "BH3-in-groove" complexes that are critical for cell death induction. Switching these residues for the corresponding residues in Bcl-2 homologous antagonist/killer (Bak) increases the binding affinity of isolated BH3 domains for pro-survival proteins; however, their exchange in the context of the parental protein causes rapid proteasomal degradation due to protein destabilization. This is supported by further x-ray crystallographic studies that capture elements of this destabilization in one pro-survival protein, Bcl-w. In pro-apoptotic Bak, we demonstrate that the corresponding distinguishing residues are important for its cell-killing capacity and antagonism by pro-survival proteins. PubMed: 25371206DOI: 10.1074/JBC.M114.610758 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
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