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Structure of the proteasome activator REGα (PA28α)

Abstract

The specificity of the 20S proteasome, which degrades many intracellular proteins, is regulated by protein complexes that bind to one or both ends of the cylindrical proteasome structure1,2,3,4,5. One of these regulatory complexes, the 11S regulator (known as REG or PA28), stimulates proteasome peptidase activity6,7 and enhances the production of antigenic peptides for presentation by class I molecules of the major histocompatibility complex (MHC)8,9. The three REG subunits that have been identified, REGα, REGβ and REGγ (also known as the Ki antigen), share extensive sequence similarity, apart from a highly variable internal segment of 17–34 residues which may confer subunit-specific properties10. REGα and REGβ preferentially form a heteromeric complex11, although purified REGα forms a heptamer in solution12 and has biochemical properties similar to the heteromeric REGα/REGβ complex13,14. We have now determined the crystal structure of human recombinant REGα at 2.8 Å resolution. The heptameric barrel-shaped assembly contains a central channel that has an opening of 20 Å diameter at one end and another of 30 Å diameter at the presumed proteasome-binding surface. The binding of REG probably causes conformational changes that open a pore in the proteasome α-subunits through which substrates and products can pass.

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Figure 1: REGα secondary structure and sequence alignment with human REGβ and REGγ.
Figure 2: Structure of REGα.
Figure 3: Structure of REGα.
Figure 4: Model for the interaction of REG with the proteasome.

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Acknowledgements

We thank D. Worthylake and M. Mathews for assistance with data collection; V. Ramakrishnan, W. Sundquist, and members of C.P.H.'s and M.R.'s laboratories for critical comments on the manuscript. This work was supported by the American Cancer Society and the Lucille P. Markey Charitable Trust, S.C.J. was an NIH predoctoral trainee.

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Correspondence to Christopher P. Hill.

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Knowlton, J., Johnston, S., Whitby, F. et al. Structure of the proteasome activator REGα (PA28α). Nature 390, 639–643 (1997). https://doi.org/10.1038/37670

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