The Hsp90 Cochaperone p23 Is the Limiting Component of the Multiprotein Hsp90/Hsp70-based Chaperone System in Vivo Where It Acts to Stabilize the Client Protein·Hsp90 Complex

Morishima, Yosuke; Kanelakis, Kimon C.; Murphy, Patrick J.; Lowe, Ezra R.; Jenkins, Gary J.; Osawa, Yoichi; Sunahara, Roger K.; Pratt, William B.

doi:10.1074/jbc.m309814200

Cited by 88 publications

(62 citation statements)

References 32 publications

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“…The Hsp90 cochaperone p23 appears to directly interact with ATP-bound form of Hsp90 and promote the maturation of client proteins (26). p23 is also found to stabilize the client protein-Hsp90 complex in vivo (33). Even though the proteins containing the p23_like domain, the core-folding motif of p23 protein may have diverse functions, most of them seem to associate with Hsp90 (25,26).…”

Section: Discussionmentioning

confidence: 99%

NudC-like protein 2 regulates the LIS1/dynein pathway by stabilizing LIS1 with Hsp90

Yang

Yan²,

Cai³

et al. 2010

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

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The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability. Thus, our results suggest that NudCL2 regulates the LIS1/dynein pathway by stabilizing LIS1 with Hsp90 chaperone. This represents a hitherto undescribed mechanism of the LIS1/dynein regulation in mammalian cells.cochaperone | heat shock protein 90 | lissencephaly 1 | migration | p23

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Section: Discussionmentioning

confidence: 99%

NudC-like protein 2 regulates the LIS1/dynein pathway by stabilizing LIS1 with Hsp90

Yang

Yan²,

Cai³

et al. 2010

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

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“…The functional consequences of these regulatory cochaperones are less clear. p23 enhances Hsp90-dependent folding, and it is thought to stabilize substrate-binding by Hsp90, yet after ATP hydrolysis, p23 promotes Hsp90 dissociation from substrate (Young and Hartl, 2000;Sullivan et al, 2002;Morishima et al, 2003). Aha1 also enhances Hsp90 function in vivo, but it has been proposed to also dissociate Hsp90 from substrate (Panaretou et al, 2002;Lotz et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Cochaperones that do not belong to these structural families include Cdc37, p23, and Aha1. p23 stabilizes the ATP-and substrate-binding state of Hsp90, whereas the recently discovered Aha1 stimulates the Hsp90 ATPase (Panaretou et al, 2002;Sullivan et al, 2002;Lotz et al, 2003;Morishima et al, 2003;Pearl and Prodromou, 2006).…”

Section: Introductionmentioning

confidence: 99%

Multiple 40-kDa Heat-Shock Protein Chaperones Function in Tom70-dependent Mitochondrial Import

Bhangoo

Tzankov

Fan

et al. 2007

MBoC

108

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Mitochondrial preproteins that are imported via the translocase of the mitochondrial outer membrane (Tom)70 receptor are complexed with cytosolic chaperones before targeting to the mitochondrial outer membrane. The adenine nucleotide transporter (ANT) follows this pathway, and its purified mature form is identical to the preprotein. Purified ANT was reconstituted with chaperones in reticulocyte lysate, and bound proteins were identified by mass spectrometry. In addition to 70-kDa heat-shock cognate protein (Hsc70) and 90-kDa heat-shock protein (Hsp90), a specific subset of cochaperones were found, but no mitochondria-specific targeting factors were found. Interestingly, three different Hsp40-related J-domain proteins were identified: DJA1, DJA2, and DJA4. The DJAs bound preproteins to different extents through their C-terminal regions. DJA dominant-negative mutants lacking the N-terminal J-domains impaired mitochondrial import. The mutants blocked the binding of Hsc70 to preprotein, but with varying efficiency. The DJAs also showed significant differences in activation of the Hsc70 ATPase and Hsc70-dependent protein refolding. In HeLa cells, the DJAs increased new protein folding and mitochondrial import, although to different extents. No single DJA was superior to the others in all aspects, but each had a profile of partial specialization. The Hsp90 cochaperones p23 and Aha1 also regulated Hsp90 -preprotein interactions. We suggest that multiple cochaperones with similar yet partially specialized properties cooperate in optimal chaperone-preprotein complexes.

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“…Therefore, hsp90 has emerged as a promising target in cancer therapy (2). Activation of client proteins by hsp90-based chaperone machine involves an ordered association with several cochaperones, e.g., p23, cdc37, and Aha-1, linked to the ATPase cycle of hsp90, which may also direct client protein specificity (3)(4)(5). Hsp90 exists predominantly as a homodimer, with transient association between NH 2 -terminal domains, thus functioning as a dimeric ''molecular clamp'' (6).…”

Section: Introductionmentioning

confidence: 99%

Role of Acetylation and Extracellular Location of Heat Shock Protein 90α in Tumor Cell Invasion

Yang¹,

Rao²,

et al. 2008

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Heat shock protein (hsp) 90 is an ATP-dependent molecular chaperone that maintains the active conformation of client oncoproteins in cancer cells. An isoform, hsp90A, promotes extracellular maturation of matrix metalloproteinase (MMP)-2, involved in tumor invasion and metastasis. Knockdown of histone deacetylase (HDAC) 6, which deacetylates lysine residues in hsp90, induces reversible hyperacetylation and attenuates ATP binding and chaperone function of hsp90. Here, using mass spectrometry, we identified seven lysine residues in hsp90A that are hyperacetylated after treatment of eukaryotic cells with a pan-HDAC inhibitor that also inhibits HDAC6. Depending on the specific lysine residue in the middle domain involved, although acetylation affects ATP, cochaperone, and client protein binding to hsp90A, acetylation of all seven lysines increased the binding of hsp90A to 17-allyl-amino-demethoxy geldanamycin. Notably, after treatment with the pan-HDAC inhibitor panobinostat (LBH589), the extracellular hsp90A was hyperacetylated and it bound to MMP-2, which was associated with increased in vitro tumor cell invasiveness. Treatment with antiacetylated hsp90A antibody inhibited in vitro invasion by tumor cells. Thus, reversible hyperacetylation modulates the intracellular and extracellular chaperone function of hsp90, and targeting extracellular hyperacetylated hsp90A may undermine tumor invasion and metastasis. [Cancer Res 2008;68(12):4833-42]

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The Hsp90 Cochaperone p23 Is the Limiting Component of the Multiprotein Hsp90/Hsp70-based Chaperone System in Vivo Where It Acts to Stabilize the Client Protein·Hsp90 Complex

Cited by 88 publications

References 32 publications

NudC-like protein 2 regulates the LIS1/dynein pathway by stabilizing LIS1 with Hsp90

NudC-like protein 2 regulates the LIS1/dynein pathway by stabilizing LIS1 with Hsp90

Multiple 40-kDa Heat-Shock Protein Chaperones Function in Tom70-dependent Mitochondrial Import

Role of Acetylation and Extracellular Location of Heat Shock Protein 90α in Tumor Cell Invasion

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