2M04

Solution structure of BCL-xL in complex with PUMA BH3 peptide

Summary for 2M04

• Entry DOI: 10.2210/pdb2m04/pdb
• Related: 2M03 4HNJ
• NMR Information: BMRB: 18793
• Descriptor: Bcl-2-like protein 1, Bcl-2-binding component 3 (2 entities in total)
• Functional Keywords: bcl-xl, puma, apoptosis-protein binding complex, apoptosis/protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Mitochondrion membrane; Single-pass membrane protein: Q07817; Mitochondrion: Q9BXH1
• Total number of polymer chains: 2
• Total formula weight: 23727.05

Authors

Viacava Follis, A.,Royappa, G.,Kriwacki, R.W. (deposition date: 2012-10-19, release date: 2013-01-30, Last modification date: 2024-05-01)

Primary citation

Follis, A.V.,Chipuk, J.E.,Fisher, J.C.,Yun, M.K.,Grace, C.R.,Nourse, A.,Baran, K.,Ou, L.,Min, L.,White, S.W.,Green, D.R.,Kriwacki, R.W.
PUMA binding induces partial unfolding within BCL-xL to disrupt p53 binding and promote apoptosis.
Nat.Chem.Biol., 9:163-168, 2013

PubMed Abstract: Following DNA damage, nuclear p53 induces the expression of PUMA, a BH3-only protein that binds and inhibits the antiapoptotic BCL-2 repertoire, including BCL-xL. PUMA, unique among BH3-only proteins, disrupts the interaction between cytosolic p53 and BCL-xL, allowing p53 to promote apoptosis via direct activation of the BCL-2 effector molecules BAX and BAK. Structural investigations using NMR spectroscopy and X-ray crystallography revealed that PUMA binding induced partial unfolding of two α-helices within BCL-xL. Wild-type PUMA or a PUMA mutant incapable of causing binding-induced unfolding of BCL-xL equivalently inhibited the antiapoptotic BCL-2 repertoire to sensitize for death receptor-activated apoptosis, but only wild-type PUMA promoted p53-dependent, DNA damage-induced apoptosis. Our data suggest that PUMA-induced partial unfolding of BCL-xL disrupts interactions between cytosolic p53 and BCL-xL, releasing the bound p53 to initiate apoptosis. We propose that regulated unfolding of BCL-xL provides a mechanism to promote PUMA-dependent signaling within the apoptotic pathways.

PubMed: 23340338
DOI: 10.1038/nchembio.1166

Experimental method

SOLUTION NMR