3PK1

Crystal structure of Mcl-1 in complex with the BaxBH3 domain

Summary for 3PK1

• Entry DOI: 10.2210/pdb3pk1/pdb
• Related: 3PL7
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, Apoptosis regulator BAX, CADMIUM ION, ... (4 entities in total)
• Functional Keywords: bcl-2 family fold, regulation of apoptosis, bax, mitochondria, apoptosis-apoptosis regulator complex, apoptosis/apoptosis regulator
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass membrane protein (Potential): Q07820; Isoform Alpha: Mitochondrion membrane; Single-pass membrane protein. Isoform Beta: Cytoplasm. Isoform Gamma: Cytoplasm. Isoform Delta: Cytoplasm (Potential): Q07812
• Total number of polymer chains: 4
• Total formula weight: 52254.30

Authors

Czabotar, P.E.,Colman, P.M. (deposition date: 2010-11-11, release date: 2010-12-29, Last modification date: 2023-11-01)

Primary citation

Czabotar, P.E.,Lee, E.F.,Thompson, G.V.,Wardak, A.Z.,Fairlie, W.D.,Colman, P.M.
Mutation to Bax beyond the BH3 domain disrupts interactions with pro-survival proteins and promotes apoptosis
J.Biol.Chem., 286:7123-7131, 2011

PubMed Abstract: Pro-survival members of the Bcl-2 family of proteins restrain the pro-apoptotic activity of Bax, either directly through interactions with Bax or indirectly by sequestration of activator BH3-only proteins, or both. Mutations in Bax that promote apoptosis can provide insight into how Bax is regulated. Here, we describe crystal structures of the pro-survival proteins Mcl-1 and Bcl-x(L) in complex with a 34-mer peptide from Bax that encompasses its BH3 domain. These structures reveal canonical interactions between four signature hydrophobic amino acids from the BaxBH3 domain and the BH3-binding groove of the pro-survival proteins. In both structures, Met-74 from the Bax peptide engages with the BH3-binding groove in a fifth hydrophobic interaction. Various Bax Met-74 mutants disrupt interactions between Bax and all pro-survival proteins, but these Bax mutants retain pro-apoptotic activity. Bax/Bak-deficient mouse embryonic fibroblast cells reconstituted with several Bax Met-74 mutants are more sensitive to the BH3 mimetic compound ABT-737 as compared with cells expressing wild-type Bax. Furthermore, the cells expressing Bax Met-74 mutants are less viable in colony assays even in the absence of an external apoptotic stimulus. These results support a model in which direct restraint of Bax by pro-survival Bcl-2 proteins is a barrier to apoptosis.

PubMed: 21199865
DOI: 10.1074/jbc.M110.161281

Experimental method

X-RAY DIFFRACTION (2.486 Å)