title: Pin1-Induced Proline Isomerization in Cytosolic p53 Mediates BAX Activation and Apoptosis.
abstract: The cytosolic fraction of the tumor suppressor p53 activates the apoptotic effector protein BAX to trigger apoptosis. Here we report that p53 activates BAX through a mechanism different from that associated with activation by BH3 only proteins (BIM and BID). We observed that cis-trans isomerization of proline 47 (Pro47) within p53, an inherently rare molecular event, was required for BAX activation. The prolyl isomerase Pin1 enhanced p53-dependent BAX activation by catalyzing cis-trans interconversion of p53 Pro47. Our results reveal a signaling mechanism whereby proline cis-trans isomerization in one protein triggers conformational and functional changes in a downstream signaling partner. Activation of BAX through the concerted action of cytosolic p53 and Pin1 may integrate cell stress signals to induce a direct apoptotic response.
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Ariele Viacava
authors.initials: AV
authors.lastname: Follis
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Llambi
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Parker
authors.initials: P
authors.lastname: Merritt
authors.affiliation: Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA; Department of Dermatology, The Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
authors.forename: Jerry E
authors.initials: JE
authors.lastname: Chipuk
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. Electronic address: douglas.green@stjude.org.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Sciences Center, 920 Court Avenue, Memphis, TN 38163, USA. Electronic address: richard.kriwacki@stjude.org.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Kriwacki
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D006801:Humans; D007700:Kinetics; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000502:physiology*; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D013237:Stereoisomerism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: C494826:BAX protein, human; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D011392:Proline; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase