title: A gradient of ATP affinities generates an asymmetric power stroke driving the chaperonin TRIC/CCT folding cycle.
abstract: The eukaryotic chaperonin TRiC/CCT uses ATP cycling to fold many essential proteins that other chaperones cannot fold. This 1 MDa hetero-oligomer consists of two identical stacked rings assembled from eight paralogous subunits, each containing a conserved ATP-binding domain. Here, we report a dramatic asymmetry in the ATP utilization cycle of this ring-shaped chaperonin, despite its apparently symmetric architecture. Only four of the eight different subunits bind ATP at physiological concentrations. ATP binding and hydrolysis by the low-affinity subunits is fully dispensable for TRiC function in vivo. The conserved nucleotide-binding hierarchy among TRiC subunits is evolutionarily modulated through differential nucleoside contacts. Strikingly, high- and low-affinity subunits are spatially segregated within two contiguous hemispheres in the ring, generating an asymmetric power stroke that drives the folding cycle. This unusual mode of ATP utilization likely serves to orchestrate a directional mechanism underlying TRiC/CCT's unique ability to fold complex eukaryotic proteins.
authors.affiliation: Department of Biology and BioX Program, Stanford University, Stanford, CA 94305-5020, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Reissmann
authors.forename: Lukasz A
authors.initials: LA
authors.lastname: Joachimiak
authors.forename: Bryan
authors.initials: B
authors.lastname: Chen
authors.forename: Anne S
authors.initials: AS
authors.lastname: Meyer
authors.forename: Anthony
authors.initials: A
authors.lastname: Nguyen
authors.forename: Judith
authors.initials: J
authors.lastname: Frydman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D002417:Cattle; D056404:Chaperonin Containing TCP-1 / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D017510:Protein Folding; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism
chemical_list: D021122:Protein Subunits; D000255:Adenosine Triphosphate; D056404:Chaperonin Containing TCP-1