2kbw
From Proteopedia
Solution Structure of human Mcl-1 complexed with human Bid_BH3 peptide
Structural highlights
Function[MCL1_HUMAN] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.[1] [BID_HUMAN] The major proteolytic product p15 BID allows the release of cytochrome c (By similarity). Isoform 1, isoform 2 and isoform 4 induce ICE-like proteases and apoptosis. Isoform 3 does not induce apoptosis. Counters the protective effect of Bcl-2.[2] Evolutionary ConservationCheck, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedMyeloid cell leukemia 1 (MCL-1), an anti-apoptotic BCL-2 family member active in the preservation of mitochondrial integrity during apoptosis, has fundamental roles in development and hematopoiesis and is dysregulated in human cancers. It bears a unique, intrinsically unstructured, N-terminal sequence, which leads to its instability in cells and hinders protein production and structural characterization. Here, we present collective data from NMR spectroscopy and titration calorimetry to reveal the selectivity of MCL-1 in binding BCL-2 homology 3 (BH3) ligands of interest for mammalian biology. The N-terminal sequence weakens the BH3 interactions but does not affect selectivity. Its removal by calpain-mediated limited proteolysis results in a stable BCL-2-like core domain of MCL-1 (cMCL-1). This core is necessary and sufficient for BH3 ligand binding. Significantly, we also characterized the in vitro protein-protein interaction between cMCL-1 and activated BID by size exclusion chromatography and NMR titrations. This interaction occurs in a very slow manner in solution but is otherwise similar to the interaction between cMCL-1 and BID-BH3 peptides. We also present the solution structure of complex cMCL-1xhBID-BH3, which completes the family portrait of MCL-1 complexes and may facilitate drug discovery against human tumors. Apoptotic regulation by MCL-1 through heterodimerization.,Liu Q, Moldoveanu T, Sprules T, Matta-Camacho E, Mansur-Azzam N, Gehring K J Biol Chem. 2010 Jun 18;285(25):19615-24. Epub 2010 Apr 14. PMID:20392693[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Large Structures | Gehring, K | Liu, Q | Mansur-Azzam, N | Matta-Camacho, E | Moldoveanu, T | Sprules, T | Alternative splicing | Apoptosis | Bid bh3 | Complex | Cytoplasm | Developmental protein | Differentiation | Mcl-1 | Membrane | Mitochondrion | Nucleus | Phosphoprotein | Polymorphism | Transmembrane | Ubl conjugation