title: PUMA binding induces partial unfolding within BCL-xL to disrupt p53 binding and promote apoptosis.
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.
authors: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Ariele Viacava
authors: AV
authors: Follis
authors: Jerry E
authors: JE
authors: Chipuk
authors: John C
authors: JC
authors: Fisher
authors: Mi-Kyung
authors: MK
authors: Yun
authors: Christy R
authors: CR
authors: Grace
authors: Amanda
authors: A
authors: Nourse
authors: Katherine
authors: K
authors: Baran
authors: Li
authors: L
authors: Ou
authors: Lie
authors: L
authors: Min
authors: Stephen W
authors: SW
authors: White
authors: Douglas R
authors: DR
authors: Green
authors: Richard W
authors: RW
authors: Kriwacki
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D058767:Protein Unfolding; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*; D051020:bcl-X Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein