Functional Specificity of Co-Chaperone Interactions with Hsp90 Client Proteins

Riggs, Daniel L.; Cox, Marc B.; Cheung‐Flynn, Joyce; Prapapanich, Viravan; Carrigan, Patricia E.; Smith, David F.

doi:10.1080/10409230490892513

Cited by 121 publications

(114 citation statements)

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“…In addition to telomerase, our work is applicable to our understanding of the p23 molecular chaperone and possibly our appreciation of the modular nature of the eukaryotic molecular chaperone network (23,24). In general, molecular chaperones mediate fundamental cellular events from nascent polypeptide folding to regulation of ''native'' proteins.…”

Section: Discussionmentioning

confidence: 98%

“…In addition to these chaperones, a plethora of Hsp90 and/or Hsp70 cofactors have been revealed. By and large, studies have addressed the impact of the associated components on the chaperone and ATPase activities of Hsp70 or Hsp90; yet, many of the constituents, including p23, Hsp104, HiP, Hdj2, Cdc37, and large immunophilins, have inherent molecular chaperone activities (23,24). For instance, Sba1p-mediated dissociation of telomerase from telomeric DNA relies on Sba1p's chaperone activity rather than on Hsp82p.…”

Section: Discussionmentioning

confidence: 99%

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The p23 molecular chaperone promotes functional telomerase complexes through DNA dissociation

Toogun

Zeiger

Freeman

2007

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

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Telomeres are the composite of short DNA element tandem arrays and heterotypic protein components that protect and maintain chromosomal termini. As proper telomere maintenance requires a multitude of DNA extension events, it is important to understand the factors that modulate telomerase DNA association. Here, we show that the endogenous levels of the yeast p23 molecular chaperone Sba1p are required for telomere length maintenance and that Sba1p can modulate telomerase DNA binding and extension activities in vitro. Notably, telomere occupancy by telomerase and the extension rate of a shortened telomere fluctuated with changing Sba1 protein levels in vivo. In addition, we found that Sba1p displayed a cell cycle-dependent telomere interaction that paralleled telomerase binding; telomere association by Sba1p depended on its inherent chaperone activity. Taken together, our results support a model in which Sba1p modulates telomerase DNA binding activity for optimal function in vitro and in vivo. DNA protein dynamicsT elomerase maintains genomic integrity, in part, by preserving chromosome length after DNA replication (1-3). Because conventional DNA polymerases require priming events to initiate synthesis, the extreme terminus of each lagging strand cannot be completed, which is commonly referred to as the end replication problem (4). In the absence of a compensatory process, this limitation would lead to chromosome erosion with each round of DNA replication. However, almost all eukaryotes circumvent this problem by adding simple DNA sequence motifs to each terminus that buffers against the loss. Typically the DNA motifs are added by the specialized ribonucleoprotein complex telomerase that is composed of a reverse transcriptase protein and an associated template RNA; in yeast, EST2 and TLC1 encode these factors. Depending on the organism, telomerase increases chromosome ends between a few hundred to a few thousand nucleotides to create, in part, a telomere. Perhaps unexpectedly, it was realized that the length of each telomere is not added at once but rather telomerase may append 6-8 nt per binding event (5). Although it had been argued that telomerase activity might not need to be iterative to maintain telomere length, recent studies in yeast indicate that telomeres can be extended over 100 nt per cell cycle (6, 7). Unfortunately, yeast telomerase does not add multiple repeats in vitro but rather extends a DNA substrate a single repeat and remains bound in a stalled state (5). Thus, the question is raised about how a bound telomerase complex is removed to allow the redundant binding and addition cycles necessary to support proper telomere maintenance.Prior studies indicated that the p23 and Hsp90 molecular chaperones are required for reconstitution of human telomerase activity in vitro (8, 9); unlike other telomerase cofactors the molecular chaperones seemingly remain associated during reverse transcription (9). A recent study indicates that the Hsp90 interaction might be necessary to promote telomerase DNA binding ...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

The p23 molecular chaperone promotes functional telomerase complexes through DNA dissociation

Toogun

Zeiger

Freeman

2007

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

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mentioning

confidence: 99%

“…The HSP90 chaperone complex also includes other HSPs, such as HSP70, and cochaperones that assist in stabilization and/or activation of client proteins (16,18). These cochaperones provide functional specificity for the HSP90 client proteins and aid in the ordered assembly of the client-HSP90 machinery (20). Most cochaperones either contain a J-domain, such as in the HSP40 cochaperones of HSP70, or have tetratricopeptide repeat (TPRs) domains as found in cochaperones that interact with HSP70 or HSP90 (21).…”

mentioning

confidence: 99%

Identification of a Novel HSP70-binding Cochaperone Critical to HSP90-mediated Activation of Small Serine/Threonine Kinase

Jha

Wong

Zerfas

et al. 2010

Journal of Biological Chemistry

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We previously reported the identification of small serine/ threonine kinase (SSTK) that is expressed in postmeiotic germ cells, associates with HSP90, and is indispensable for male fertility. Sperm from SSTK-null mice cannot fertilize eggs in vitro and are incapable of fusing with eggs that lack zona pellucida. Here, using the yeast two-hybrid screen, we have discovered a novel SSTK-interacting protein (SIP) that is expressed exclusively in testis. The gene encoding SIP is restricted to mammals and encodes a 125-amino acid polypeptide with a predicted tetratricopeptide repeat domain. SIP is co-localized with SSTK in the cytoplasm of spermatids as they undergo restructuring and chromatin condensation, but unlike SSTK, is not retained in the mature sperm. SIP binds to SSTK with high affinity (K d ϳ10 nM), and the proteins associate with each other when co-expressed in cells. In vitro, SIP inhibited SSTK kinase activity, whereas the presence of SIP in cells resulted in enzymatic activation of SSTK without affecting Akt or MAPK activity. SIP was found to be associated with cellular HSP70, and analyses with purified proteins revealed that SIP directly bound HSP70. Importantly, SSTK recruited SIP onto HSP90, and treatment of cells with the specific HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, completely abolished SSTK catalytic activity. Hence, these findings demonstrate that HSP90 is essential for functional maturation of the kinase and identify SIP as a cochaperone that is critical to the HSP90-mediated activation of SSTK.Protein phosphorylation plays important roles during spermatogenesis (1, 2). A number of protein kinases are expressed in testis, and several of them are essential for male fertility (3). For example, disruption of the Camk4 which is involved in postmeiotic chromatin condensation, results in impaired spermiogenesis and male sterility (4). Targeted deletion of the casein kinase 2␣Ј catalytic subunit leads to oligozoospermia and extensive degeneration of germ cells at all stages of spermatogenesis (5), and Cdk2 is essential for completing mitotic division in germ cells (6). Three members of the testis-specific serine threonine kinase (TSSK) 2 family, namely TSSK1, TSSK2, and the small serine/threonine kinase (SSTK, also known as TSSK6), are expressed postmeiotically and are essential for male fertility (7-13).SSTK is one of the smallest protein kinases, consists only of N-and C-lobes of a kinase catalytic domain, and forms stable associations with heat shock protein (HSP) 70 and 90 (7). Targeted deletion of Sstk in mice resulted in male infertility without any other visible somatic defects. SSTK-null sperm could not fertilize eggs in vitro and are incapable of fusing with eggs that lack zona pellucida (9). SSTK expression first appears in elongating spermatids as they undergo cellular remodeling and chromatin condensation, and the kinase is retained in mature sperm. However, the in vivo substrate(s) for SSTK, the mechanism of activation, and the specific function that SSTK performs in spe...

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“…Molecular chaperonins such as the GroE system and molecular chaperones such as the DnaK/DnaJ/ GrpE and the HtpG systems are crucial to protein folding (Riggs et al, 2004;Young et al, 2004;Zhang et al, 2002). In addition, the GroE system is thought to activate the HrcA repressor (Mogk et al, 1997;Schumann, 2000).…”

Section: Expression Of Heat-shock Genesmentioning

confidence: 99%

Heat-shock sigma factor RpoH from Geobacter sulfurreducens

Ueki

Lovley

2007

Microbiology

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Recent studies with Myxococcus xanthus have suggested that homologues of the Escherichia coli heat-shock sigma factor, RpoH, may not be involved in the heat-shock response in this d-proteobacterium. The genome of another d-proteobacterium, Geobacter sulfurreducens, which is considered to be a representative of the Fe(III)-reducing Geobacteraceae that predominate in a diversity of subsurface environments, contains an rpoH homologue. Characterization of the G. sulfurreducens rpoH homologue revealed that it was induced by a temperature shift from 30 6C to 42 6C and that an rpoH-deficient mutant was unable to grow at 42 6C. The predicted heat-shock genes, hrcA, grpE, dnaK, groES and htpG, were heat-shock inducible in an rpoH-dependent manner, and comparison of promoter regions of these genes identified the consensus sequences for the "10 and "35 promoter elements. In addition, DNA elements identical to the CIRCE consensus sequence were found in promoters of rpoH, hrcA and groES, suggesting that these genes are regulated by a homologue of the repressor HrcA, which is known to bind the CIRCE element. These results suggest that the G. sulfurreducens RpoH homologue is the heat-shock sigma factor and that heat-shock response in G. sulfurreducens is regulated positively by RpoH as well as negatively by the HrcA/CIRCE system. INTRODUCTIONThe Gram-negative d-proteobacterium Geobacter sulfurreducens is considered to be a representative of the Fe(III)-reducing Geobacteraceae that predominate in a diversity of subsurface environments where Fe(III) reduction is important . Geobacter species also play critical roles in bioremediation of groundwater contaminated with organic compounds or metals (Lloyd & Lovley, 2001;Lovley, 1997Lovley, , 2003Lovley & Coates, 1997, 2000 and in electricity production from waste organic matter (Bond et al., 2002;Bond & Lovley, 2003; Lovley, 2006a, b). However, the mechanisms they use to deal with the multiple stresses they encounter in these environments are poorly understood.Geobacter species face various environmental changes and growth conditions in the subsurface. Heat shock is a common stress to which all organisms adapt by inducing heat-shock proteins. Many heat-shock proteins are well conserved among organisms (Arrigo & Iandry, 1994;Lindquist & Craig, 1998). In bacteria, the expression of heat-shock genes is regulated in various fashions (Gross, 1996;Hecker et al., 1996;Narberhaus, 1999;Rosen & Ron, 2002;Schumann, 2000Schumann, , 2003Servant & Mazodier, 2001;Yura et al., 2000). The Gram-negative bacterium Escherichia coli uses two sigma factors, RpoH and RpoE, to activate transcription of heat-shock genes (Gross, 1996;Yura et al., 2000). The sigma factor, which is a subunit of RNA polymerase (RNAP), recognizes specific promoter elements and is essential for initiation of transcription. RpoHdependent transcription is also found in other Gramnegative bacteria (Gross, 1996;Yura et al., 2000;Rosen & Ron, 2002). The regulation of heat-shock gene expression in the Gram-positive bacterium Bacillus s...

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Functional Specificity of Co-Chaperone Interactions with Hsp90 Client Proteins

Cited by 121 publications

References 150 publications

The p23 molecular chaperone promotes functional telomerase complexes through DNA dissociation

The p23 molecular chaperone promotes functional telomerase complexes through DNA dissociation

Identification of a Novel HSP70-binding Cochaperone Critical to HSP90-mediated Activation of Small Serine/Threonine Kinase

Heat-shock sigma factor RpoH from Geobacter sulfurreducens

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