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Reference: Park S, et al. (2011) Structural defects in the regulatory particle-core particle interface of the proteasome induce a novel proteasome stress response. J Biol Chem 286(42):36652-66

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Abstract


Proteasomes consist of a 19-subunit regulatory particle (RP) and 28-subunit core particle (CP), an a(7)?(7)?(7)a(7) structure. The RP recognizes substrates and translocates them into the CP for degradation. At the RP-CP interface, a heterohexameric Rpt ring joins to a heteroheptameric CP a ring. Rpt C termini insert individually into the a ring pockets to form a salt bridge with a pocket lysine residue. We report that substitutions of a pocket lysine residues produce an unexpected block to CP assembly, arising from a late stage defect in ? ring assembly. Substitutions a5(K66A) and a6(K62A) resulted in abundant incorporation of immature CP ? subunits, associated with a complete ? ring, into proteasome holoenzymes. Incorporation of immature CP into the proteasome depended on a proteasome-associated protein, Ecm29. Using ump1 mutants, we identified Ecm29 as a potent negative regulator of RP assembly and confirmed our previous findings that proper RP assembly requires the CP. Ecm29 was enriched on proteasomes of pocket lysine mutants, as well as those of rpt4-?1 and rpt6-?1 mutants, in which the C-terminal residue, thought to contact the pocket lysine, is deleted. In both rpt6-?1 and a6(K62A) proteasomes, Ecm29 suppressed opening of the CP substrate translocation channel, which is gated through interactions between Rpt C termini and the a pockets. The ubiquitin ligase Hul5 was recruited to these proteasomes together with Ecm29. Proteasome remodeling through the addition of Ecm29 and Hul5 suggests a new layer of the proteasome stress response and may be a common response to structurally aberrant proteasomes or deficient proteasome function.

Reference Type
Journal Article | Research Support, Non-U.S. Gov't | Research Support, N.I.H., Extramural
Authors
Park S, Kim W, Tian G, Gygi SP, Finley D
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