Proteomics

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The cochaperone CHIP marks Hsp70- and Hsp90-bound substrates for degradation through a very flexible mechanism


ABSTRACT: Some molecular chaperones are involved not only in assisting the folding of proteins but also, given appropriate conditions, in their degradation. This is the case of Hsp70 and Hsp90, which direct their bound substrate to degradation through ubiquitination in concert with the cochaperone CHIP –an E3 ligase. We have generated complexes between the chaperone (Hsp70 or Hsp90), the cochaperone CHIP and, as substrate, a p53 variant containing the GST protein (p53-TMGST). The two ternary complexes (Hsp70:p53-TMGST:CHIP and Hsp90:p53-TMGST:CHIP) ubiquitinate the substrate, and this is done with a higher efficiency than in the absence of the chaperones. The 3D structures of the two complexes, obtained using a combination of cryoelectron microscopy and crosslinking mass spectrometry, show the substrate located between the chaperone and the cochaperone, which suggests an ubiquitination mechanism. Both complexes are extremely flexible, which is crucial for the ubiquitination process.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Eduard Sabidó  

LAB HEAD: Eduard Sabidó

PROVIDER: PXD009756 | Pride | 2019-03-07

REPOSITORIES: Pride

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The cochaperone CHIP marks Hsp70- and Hsp90-bound substrates for degradation through a very flexible mechanism.

Quintana-Gallardo Lucía L   Martín-Benito Jaime J   Marcilla Miguel M   Espadas Guadalupe G   Sabidó Eduard E   Valpuesta José María JM  

Scientific reports 20190325 1


Some molecular chaperones are involved not only in assisting the folding of proteins but also, given appropriate conditions, in their degradation. This is the case for Hsp70 and Hsp90 which, in concert with the cochaperone CHIP, direct their bound substrate to degradation through ubiquitination. We generated complexes between the chaperones (Hsp70 or Hsp90), the cochaperone CHIP and, as substrate, a p53 variant containing the GST protein (p53-TMGST). Both ternary complexes (Hsp70:p53-TMGST:CHIP  ...[more]

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