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PMID: 17389404 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Structural insights into the degradation of Mcl-1 induced by BH3 domains.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 104 ·No. 15 ·2007-04-10 ·Pages 6217-22

Czabotar PE, Lee EF, van Delft MF, Day CL, Smith BJ, Huang DC, Fairlie WD, Hinds MG, Colman PM

Abstract

Apoptosis is held in check by prosurvival proteins of the Bcl-2 family. The distantly related BH3-only proteins bind to and antagonize them, thereby promoting apoptosis. Whereas binding of the BH3-only protein Noxa to prosurvival Mcl-1 induces Mcl-1 degradation by the proteasome, binding of another BH3-only ligand, Bim, elevates Mcl-1 protein levels. We compared the three-dimensional structures of the complexes formed between BH3 peptides of both Bim and Noxa, and we show that a discrete C-terminal sequence of the Noxa BH3 is necessary to instigate Mcl-1 degradation.

MeSH Terms
Amino Acid Sequence Animals Apoptosis/genetics Apoptosis Regulatory Proteins/metabolism Bcl-2-Like Protein 11 Crystallography Humans Membrane Proteins/metabolism Mice Models, Molecular Molecular Sequence Data Multiprotein Complexes/chemistry,metabolism Myeloid Cell Leukemia Sequence 1 Protein Neoplasm Proteins/chemistry,metabolism Nuclear Magnetic Resonance, Biomolecular Protein Structure, Tertiary Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-bcl-2/chemistry,metabolism Recombinant Fusion Proteins/chemistry,metabolism
Chemicals
Apoptosis Regulatory Proteins BCL2L11 protein, human Bcl-2-Like Protein 11 Bcl2l11 protein, mouse Mcl1 protein, mouse Membrane Proteins Multiprotein Complexes Myeloid Cell Leukemia Sequence 1 Protein Neoplasm Proteins PMAIP1 protein, human Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Recombinant Fusion Proteins
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Czabotar Peter E
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
Lee Erinna F
van Delft Mark F
Day Catherine L
Smith Brian J
Huang David C S
Fairlie W Douglas
Hinds Mark G
Colman Peter M
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0701297104
Published
2007-04-10
Epub
2007-00-27
Pages
6217-22
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1851040
Subset
IM
Grants
Wellcome Trust · United Kingdom
NCI NIH HHS · R01 CA080188 · United States
NCI NIH HHS · CA80188 · United States
Databases
PDB
2JM6, 2NL9, 2NLA
External Links
PubMed source DOI: 10.1073/pnas.0701297104 PMC Full Text View journal details
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