The N-terminal Zinc Binding Domain of ClpX Is a Dimerization Domain That Modulates the Chaperone Function

Wojtyra, Urszula; Thibault, Guillaume; Tuite, Ashleigh R.; Houry, Walid

doi:10.1074/jbc.m307825200

Cited by 103 publications

(142 citation statements)

References 43 publications

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“…6A, which is published as supporting information on the PNAS web site). The importance of the N-terminal domain of ClpX is evident from its absolute conservation across all sequenced genomes (4). Our group demonstrated that the N-terminal domain of ClpX is a C4-type zinc-binding domain (ZBD) that forms a very stable constitutive symmetric dimer in isolation and in full-length ClpX.…”

mentioning

confidence: 99%

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Specificity in substrate and cofactor recognition by the N-terminal domain of the chaperone ClpX

Thibault

Yudin²,

Wong³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Clp ATPases are a unique group of ATP-dependent chaperones supporting targeted protein unfolding and degradation in concert with their respective proteases. ClpX is a representative member of these ATPases; it consists of two domains, a zinc-binding domain (ZBD) that forms dimers and a AAA ؉ ATP-binding domain that arranges into a hexamer. Analysis of the binding preferences of these two domains in ClpX revealed that both domains preferentially bind to hydrophobic residues but have different sequence preferences, with the AAA ؉ domain preferentially recognizing a wider range of specific sequences than ZBD. As part of this analysis, the binding site of the ClpX dimeric cofactor, SspB 2, on ZBD in ClpX was determined by NMR and mutational analysis. The SspB C terminus was found to interact with a hydrophobic patch on the surface of ZBD. The affinity of SspB 2 toward ZBD2 and the geometry of the SspB 2-ZBD2 complex were investigated by using the newly developed quantitative optical biosensor method of dual polarization interferometry. The data suggest a model for the interaction between SspB 2 and the ClpX hexamer.

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mentioning

confidence: 99%

“…Our group demonstrated that the N-terminal domain of ClpX is a C4-type zinc-binding domain (ZBD) that forms a very stable constitutive symmetric dimer in isolation and in full-length ClpX. ZBD binds one Zn(II) per monomer (4,5). Hydrophobic residues that form the interface between two ZBD monomers are highly conserved throughout the sequenced genomes (5).…”

mentioning

confidence: 99%

Specificity in substrate and cofactor recognition by the N-terminal domain of the chaperone ClpX

Thibault

Yudin²,

Wong³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…16 Moreover, the C-terminal residues of the phage MuA protein (LDILEQNRRKKAI 662 ) target it for ClpXP degradation in a partially N-domain-dependent manner and share homology with the Cc SspBa XB peptide. 12,18,35 Peptide-binding domains (PDZ, WW, SH2, SH3, PTB, FHA, 14-3-3, EVH1, etc.) are used in modular fashions in an enormous number of biological processes to ensure specificity.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11] Each ClpX subunit consists of an AAAþ domain and a ClpX-family-specific N-terminal domain, which binds zinc via a conserved set of cysteine residues and forms a stable dimer. 12,13 ClpX lacking the N domain (ClpX DN ) can still bind ClpP and power degradation of some substrates, 12,14 establishing that the N domain is not required for the basic enzymatic functions of ClpX. However, ClpX DN fails to recognize certain substrates and does not support degradation mediated by many adaptors.…”

Section: Introductionmentioning

confidence: 99%

“…However, ClpX DN fails to recognize certain substrates and does not support degradation mediated by many adaptors. 10,12,[14][15][16][17][18] SspB consists of a dimeric substrate-binding domain, followed by a flexible linker and a C-terminal peptide that binds to the ClpX N domain. 8,15,[19][20][21][22][23] By binding to ClpX and specific substrates, simultaneously, SspB increases the local concentration of substrate relative to the protease.…”

Section: Introductionmentioning

confidence: 99%

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Versatile modes of peptide recognition by the ClpX N domain mediate alternative adaptor‐binding specificities in different bacterial species

et al. 2010

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ClpXP, an AAA1 protease, plays key roles in protein-quality control and many regulatory processes in bacteria. The N-terminal domain of the ClpX component of ClpXP is involved in recognition of many protein substrates, either directly or by binding the SspB adaptor protein, which delivers specific classes of substrates for degradation. Despite very limited sequence homology between the E. coli and C. crescentus SspB orthologs, each of these adaptors can deliver substrates to the ClpXP enzyme from the other bacterial species. We show that the ClpX N domain recognizes different sequence determinants in the ClpX-binding (XB) peptides of C. crescentus SspBa and E. coli SspB. The C. crescentus XB determinants span 10 residues and involve interactions with multiple side chains, whereas the E. coli XB determinants span half as many residues with only a few important side chain contacts. These results demonstrate that the N domain of ClpX functions as a highly versatile platform for peptide recognition, allowing the emergence during evolution of alternative adaptor-binding specificities. Our results also reveal highly conserved residues in the XB peptides of both E. coli SspB and C. crescentus SspBa that play no detectable role in ClpX-binding or substrate delivery.

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Structural Studies of Large, Self‐Compartmentalizing Proteases

Rockel

Bosch

Baumeister

2007

Protein Degradation Series

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The N-terminal Zinc Binding Domain of ClpX Is a Dimerization Domain That Modulates the Chaperone Function

Cited by 103 publications

References 43 publications

Specificity in substrate and cofactor recognition by the N-terminal domain of the chaperone ClpX

Specificity in substrate and cofactor recognition by the N-terminal domain of the chaperone ClpX

Versatile modes of peptide recognition by the ClpX N domain mediate alternative adaptor‐binding specificities in different bacterial species

Structural Studies of Large, Self‐Compartmentalizing Proteases

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