title: Programmed cell death protein 5 interacts with the cytosolic chaperonin containing tailless complex polypeptide 1 (CCT) to regulate β-tubulin folding.
abstract: Programmed cell death protein 5 (PDCD5) has been proposed to act as a pro-apoptotic factor and tumor suppressor. However, the mechanisms underlying its apoptotic function are largely unknown. A proteomics search for binding partners of phosducin-like protein, a co-chaperone for the cytosolic chaperonin containing tailless complex polypeptide 1 (CCT), revealed a robust interaction between PDCD5 and CCT. PDCD5 formed a complex with CCT and β-tubulin, a key CCT-folding substrate, and specifically inhibited β-tubulin folding. Cryo-electron microscopy studies of the PDCD5·CCT complex suggested a possible mechanism of inhibition of β-tubulin folding. PDCD5 bound the apical domain of the CCTβ subunit, projecting above the folding cavity without entering it. Like PDCD5, β-tubulin also interacts with the CCTβ apical domain, but a second site is found at the sensor loop deep within the folding cavity. These orientations of PDCD5 and β-tubulin suggest that PDCD5 sterically interferes with β-tubulin binding to the CCTβ apical domain and inhibits β-tubulin folding. Given the importance of tubulins in cell division and proliferation, PDCD5 might exert its apoptotic function at least in part through inhibition of β-tubulin folding.
authors.affiliation: From the Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Tracy
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Gray
authors.forename: Jorge
authors.initials: J
authors.lastname: Cuéllar
authors.forename: Tanner S
authors.initials: TS
authors.lastname: Shaw
authors.forename: Alyson C
authors.initials: AC
authors.lastname: Howlett
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Taylor
authors.forename: John T
authors.initials: JT
authors.lastname: Prince
authors.forename: Natalie G
authors.initials: NG
authors.lastname: Ahn
authors.forename: José M
authors.initials: JM
authors.lastname: Valpuesta
authors.forename: Barry M
authors.initials: BM
authors.lastname: Willardson
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D056404:Chaperonin Containing TCP-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C533298:CCT2 protein, human; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; C117283:PDCD5 protein, human; D014404:Tubulin; D056404:Chaperonin Containing TCP-1
keywords: Apoptosis; Chaperone Chaperonin; Electron Microscopy (EM); Programmed Cell Death Protein 5; Protein Folding; Tubulin