2013
DOI: 10.1021/bi4009209
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The E3 Ubiquitin Ligase CHIP and the Molecular Chaperone Hsc70 Form a Dynamic, Tethered Complex

Abstract: The E3 ubiquitin ligase CHIP (C-terminus of Hsc70 Interacting Protein, a 70 kDa homodimer) binds to the molecular chaperone Hsc70 (a 70 kDa monomer) and this complex is important in both the ubiquitination of Hsc70 and the turnover of Hsc70-bound clients. Here we used NMR spectroscopy, bio-layer interferometry, and fluorescence polarization to characterize the Hsc70-CHIP interaction. We found that CHIP binds tightly to two molecules of Hsc70 forming a 210 kDa complex, with a Kd of approximately 60 nM, and that… Show more

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Cited by 51 publications
(76 citation statements)
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“…Although it is not practical to dissect the kinetics of this multicomponent complex using the current experimental system, increased CHIPmediated ubiquitination of ERa tethered to Hsp70 through AptHsp70-ER-1 suggests that substrate ubiquitination may not require strict geometric arrangement of the substrate with respect to Hsp70 and CHIP. This is consistent with a previous study, which suggested that CHIP forms a dynamic complex with Hsp70 to search a large space for ubiquitinating Hsp70 substrates [37].…”
Section: A Bifunctional Aptamer Is Created To Connect Hsp70 With Erasupporting
confidence: 93%
“…Although it is not practical to dissect the kinetics of this multicomponent complex using the current experimental system, increased CHIPmediated ubiquitination of ERa tethered to Hsp70 through AptHsp70-ER-1 suggests that substrate ubiquitination may not require strict geometric arrangement of the substrate with respect to Hsp70 and CHIP. This is consistent with a previous study, which suggested that CHIP forms a dynamic complex with Hsp70 to search a large space for ubiquitinating Hsp70 substrates [37].…”
Section: A Bifunctional Aptamer Is Created To Connect Hsp70 With Erasupporting
confidence: 93%
“…hsc-70 carries out each of these activities by interacting with a different set of molecular partners. Although the interaction partners and co-chaperones involved in folding and proteasomal degradation are beginning to be understood (2,6,7,10,11,15), the interactions that link hsc-70 to autophagy are much less clear. What is known is that hsc-70 interacts with p62 in the autophagosome to deliver its ubiquitinated cargo through macroautophagy (8), with PS on the endosomal limiting membrane to mediate eMI (21) and that it interacts with lysosomal associate membrane protein type 2A for chaperone-mediated autophagy (8,21,22).…”
Section: Discussionmentioning
confidence: 99%
“…Nucleotides (ATP and ADP) bind into a deep pocket in the NBD (29); hydrophobic substrates (unfolded proteins) bind to a hydrophobic cleft in the SBD that is guarded by the LID (30). J-proteins (such as DnaJA1 and DnaJB4) affect the interaction between the NBD and SBD by locating into the area between them (19, 31); nucleotide exchange factors of the BAG family (BAG 1, 3, and 6) interact with tips of the NBD domain lobes (32, 33); the E3-ubiquitin ligase CHIP interacts with the very C terminus (15). Potent synthetic regulators derived from the rhodamine MKT077 interact with a conserved site close to the nucleotide-binding site in hsc-70 (34,35).…”
Section: Discussionmentioning
confidence: 99%
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