Closing the folding chamber of the eukaryotic chaperonin requires the transition state of ATP hydrolysis.
Chaperonins use ATPase cycling to promote conformational changes leading to protein folding. The prokaryotic chaperonin GroEL requires a cofactor, GroES, which serves as a "lid" enclosing substrates in the central cavity and confers an asymmetry on GroEL required for cooperative transitions driving the reaction. The eukaryotic chaperonin TRiC/CCT does not have such a cofactor but appears to have a "built-in" lid. Whether this seemingly symmetric chaperonin also operates through an asymmetric cycle is unclear. We show that unlike GroEL, TRiC does not close its lid upon nucleotide binding, but instead responds to the trigonal-bipyramidal transition state of ATP hydrolysis. Further, nucleotide analogs inducing this transition state confer an asymmetric conformation on TRiC. Similar to GroEL, lid closure in TRiC confines the substrates in the cavity and is essential for folding. Understanding the distinct mechanisms governing eukaryotic and bacterial chaperonin function may reveal how TRiC has evolved to fold specific eukaryotic proteins.
Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.
Anne S
AS
Meyer
Joel R
JR
Gillespie
Dirk
D
Walther
Ian S
IS
Millet
Sebastian
S
Doniach
Judith
J
Frydman
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D006868:Hydrolysis; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D013329:Structure-Activity Relationship; D044767:Ubiquitin-Protein Ligases; D014961:X-Ray Diffraction; D056427:t-Complex Genome Region
D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D000255:Adenosine Triphosphate; C116196:PPP1R11 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases