Mapping the specific cytoprotective interaction of humanin with the pro-apoptotic protein bid.
Humanin is a short endogenous peptide, which can provide protection from cell death through its association with various receptors, including the pro-apoptotic Bcl-2 family proteins Bid, Bim, and Bax. By using NMR chemical shift mapping experiments, we demonstrate that the interaction between Humanin-derived peptides and Bid is specific, and we localize the binding site to a region on the surface of Bid, which includes residues from the conserved helical BH3 domain of the protein. The BH3 domain mediates the association of Bid with other Bcl-2 family members and is essential for the protein's cytotoxic activity. The data suggest that Humanin exerts its cytoprotective activity by engaging the Bid BH3 domain; this would hinder the association of Bid with other Bcl-2 family proteins, thereby mitigating its toxicity. The identification of a Humanin-specific binding site on the surface of Bid reinforces its importance as a direct modulator of programmed cell death, and suggests a strategy for the design of cytoprotective peptide inhibitors of Bid.
Choi
Jungyuen
J
Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Zhai
Dayong
D
Zhou
Xin
X
Satterthwait
Arnold
A
Reed
John C
JC
Marassi
Francesca M
FM
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000737:chemistry*; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death / Q000502:physiology; D017124:Conserved Sequence; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000502:physiology*; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D051028:bcl-2-Associated X Protein / Q000737:chemistry*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051028:bcl-2-Associated X Protein; C427211:humanin