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Conformational dynamics of the Rpt6 ATPase in proteasome assembly and Rpn14 binding.

Juxtaposed to either or both ends of the proteasome core particle (CP) can exist a 19S regulatory particle (RP) that recognizes and prepares ubiquitinated proteins for proteolysis. RP triphosphatase proteins (Rpt1-Rpt6), which are critical for substrate translocation into the CP, bind chaperone-like proteins (Hsm3, Nas2, Nas6, and Rpn14) implicated in RP assembly. We used NMR and other biophysical methods to reveal that S. cerevisiae Rpt6's C-terminal domain undergoes dynamic helix-coil transitions enabled by helix-destabilizing glycines within its two most C-terminal α helices. Rpn14 binds selectively to Rpt6's four-helix bundle, with surprisingly high affinity. Loss of Rpt6's partially unfolded state by glycine substitution (Rpt6 G³⁶⁰,³⁸⁷A) disrupts holoenzyme formation in vitro, an effect enhanced by Rpn14. S. cerevisiae lacking Rpn14 and incorporating Rpt6 G³⁶⁰,³⁸⁷A demonstrate hallmarks of defective proteasome assembly and synthetic growth defects. Rpt4 and Rpt5 exhibit similar exchange, suggesting that conserved structural heterogeneity among Rpt proteins may facilitate RP-CP assembly.

Pubmed ID: 23562395 RIS Download

Mesh terms: Adenosine Triphosphatases | Binding Sites | Carrier Proteins | Glycine | Models, Molecular | Proteasome Endopeptidase Complex | Protein Conformation | Saccharomyces cerevisiae | Saccharomyces cerevisiae Proteins

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Associated grants

  • Agency: NCI NIH HHS, Id: CA097004
  • Agency: NIGMS NIH HHS, Id: R01 GM043601
  • Agency: NCI NIH HHS, Id: R01 CA097004
  • Agency: NCI NIH HHS, Id: R01 CA136472
  • Agency: NIGMS NIH HHS, Id: R37 GM043601
  • Agency: NCI NIH HHS, Id: CA136472
  • Agency: NIGMS NIH HHS, Id: GM043601

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