2KBW

Solution Structure of human Mcl-1 complexed with human Bid_BH3 peptide

2KBW の概要

• エントリーDOI: 10.2210/pdb2kbw/pdb
• 関連するPDBエントリー: 1wsx
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1, BH3-interacting domain death agonist (2 entities in total)
• 機能のキーワード: mcl-1, bid_bh3, complex, alternative splicing, apoptosis, cytoplasm, developmental protein, differentiation, membrane, mitochondrion, nucleus, phosphoprotein, polymorphism, transmembrane, ubl conjugation
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Membrane; Single-pass membrane protein (Potential): Q07820; Cytoplasm (By similarity). BH3-interacting domain death agonist p15: Mitochondrion membrane (By similarity). BH3-interacting domain death agonist p13: Mitochondrion membrane (By similarity). Isoform 1: Cytoplasm. Isoform 3: Cytoplasm. Isoform 2: Mitochondrion membrane: P55957
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22449.34

構造登録者

Liu, Q.,Moldoveanu, T.,Sprules, T.,Matta-Camacho, E.,Mansur-Azzam, N.,Gehring, K. (登録日: 2008-12-09, 公開日: 2009-12-15, 最終更新日: 2024-05-22)

主引用文献

Liu, Q.,Moldoveanu, T.,Sprules, T.,Matta-Camacho, E.,Mansur-Azzam, N.,Gehring, K.
Apoptotic regulation by MCL-1 through heterodimerization.
J.Biol.Chem., 285:19615-19624, 2010

PubMed Abstract: Myeloid 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.

PubMed: 20392693
DOI: 10.1074/jbc.M110.105452

実験手法

SOLUTION NMR