Interaction of Hsp90 with 20S proteasome: Thermodynamic and kinetic characterization

Eleuteri, Anna Maria; Cuccioloni, Massimiliano; Bellesi, J.; Lupidi, Giulio; Fioretti, Evandro; Angeletti, Mauro

doi:10.1002/prot.10101

Cited by 35 publications

(31 citation statements)

References 38 publications

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“…46 The α-subunits make-up the two outer rings of the complex. Because these subunits are part of every catalytic core, their content provides a valid estimate of the total amount of proteasome present in the cell.…”

Section: Resultsmentioning

confidence: 99%

Changes in Select Redox Proteins of the Retinal Pigment Epithelium in Age-related Macular Degeneration

Decanini

Nordgaard

Feng

et al. 2007

American Journal of Ophthalmology

136

104

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PURPOSE-To examine changes of select reduction-oxidation (redox) sensitive proteins from human donor retinal pigment epithelium (RPE) at four stages of age-related macular degeneration (AMD). DESIGN-Experimental study.METHODS-Human donor eyes were obtained from the Minnesota Lions Eye Bank and graded using the Minnesota Grading System (MGS) into four stages that correspond to stages defined by the age-related eye disease study (AREDS). Protein content in RPE homogenates was measured using Western immunoblotting with protein-specific antibodies.RESULTS-The content of several antioxidant enzymes and specific proteins that facilitate refolding or degradation of oxidatively damaged proteins increased significantly in MGS stage 3. These proteins are involved in the primary (copper-zinc superoxide dismutase [CuZnSOD], manganese superoxide dismutase [MnSOD], and catalase) and secondary (heat shock protein [HSP] 27, HSP 90, and proteasome) defense against oxidative damage. Additionally, the insulin prosurvival receptor exhibited disease-related upregulation.CONCLUSIONS-The pattern of protein changes identified in human donor tissue graded using the MGS support the role of oxidative mechanisms in the pathogenesis and progression of AMD. The MGS uses nearly identical clinical definitions and grading criteria of AMD that are used in the AREDS, so our results apply to clinical and epidemiologic studies using similar definitions. Results from our protein analysis of human donor tissue helps to explain altered oxidative stress regulation and cell-survival pathways that occur in progressive stages of AMD.Age-related macular degeneration (amd) is the leading cause of blindness in developed countries 1-9 . The number of affected individuals in the United States alone is expected to increase nearly twofold, to approximately three million by the year 2020. 10 Fortunately, therapeutic options are improving. The use of antioxidant vitamins has been shown to delay disease progression at an intermediate stage, 11 and rapid innovation in the use of antiangiogenic therapies has resulted in new clinical methods to treat the exudative phase of AMD. 12-18 However, developing new treatment and prevention strategies targeting earlier stages of the disease requires a better understanding of the underlying disease mechanisms.Findings from the Age-Related Eye Disease Study (AREDS) clearly support the hypothesis that oxidative mechanisms play a significant role in the progression of AMD. Although several studies have shown that the intake of antioxidant-rich foods lowers the risk of AMD, 19-24 others have not supported this conclusion. 25-27 Cigarette smoking, a pro-oxidant, NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript significantly increases the risk of AMD, and this association is well supported in numerous, well-designed studies. 28-35The retinal pigment epithelium (RPE) is subject to a particularly high level of oxidative stress because of locally elevated oxygen tension, high polyunsaturated lipid con...

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Section: Resultsmentioning

confidence: 99%

Changes in Select Redox Proteins of the Retinal Pigment Epithelium in Age-related Macular Degeneration

Decanini

Nordgaard

Feng

et al. 2007

American Journal of Ophthalmology

136

104

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“…HSP90 is known to associate with large protein complexes including the proteasome, SCF complex and the components of the centromere-binding factor 3 (CBF3) kinetochore (39)(40)(41). Biochemical functions of HSP90 in these complexes are still unknown.…”

Section: Hsp90 Is Essential For Rps2-dependent Resistancementioning

confidence: 99%

HSP90 interacts with RAR1 and SGT1 and is essential for RPS2-mediated disease resistance in Arabidopsis

Takahashi

Casais

Ichimura

et al. 2003

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

442

423

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RAR1 and its interacting partner SGT1 play a central role in plant disease resistance triggered by a number of resistance (R) proteins. We identified cytosolic heat shock protein 90 (HSP90), a molecular chaperone, as another RAR1 interacting protein by yeast twohybrid screening. RAR1 interacts with the N-terminal half of HSP90 that contains the ATPase domain. HSP90 also specifically interacts with SGT1 that contains a tetratricopeptide repeat motif and a domain with similarity to the cochaperone p23. In Arabidopsis, the HSP90 inhibitor geldanamycin reduces the hypersensitive response and abolishes resistance triggered by the R protein RPS2 against Pseudomonas syringae pv. tomato DC3000 (avrRpt2). One of four Arabidopsis cytosolic HSP90 isoforms, AtHSP90.1 is required for full RPS2 resistance and is rapidly induced upon pathogen challenge. We propose that RAR1 and SGT1 function closely with HSP90 in chaperoning roles that are essential for disease resistance.

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“…4). Given the high affinity association between Hsp90 and the 20 S proteasome (K d Ͻ 100 nM) (21,23,(32)(33)(34), the maximal activation of 20 S proteasome degradative activity in the presence of four Hsp90 molecules suggests the occupancy of all regulatory sites on the 20 S proteasome. The lack of any additional activation in the presence of excess Hsp90 argues against an indirect role, in which Hsp90 binding to CaM ox would, for example, expose specific binding sites on CaM ox that result in targeted protein degradation by the 20 S proteasome.…”

Section: Oxidized Cam As a Substrate For The 20 S Proteasome-mentioning

confidence: 99%

“…Binding of the regulatory 11 S REG or 19 S protein complexes to the ␣-subunits of the 20 S proteasome stabilizes the open conformation and facilitates regulated substrate access (16,20). The chaperone Hsp90 has also been suggested to bind the ␣-subunits of the 20 S proteasome and to function as a regulator of proteasome function (21)(22)(23). Thus, observed cellular linkages between Hsp90 function and the rates of protein degradation may involve both the stabilization of partially unfolded proteins as well as a direct modulation of protein degradation by the proteasome (24 -31).…”

mentioning

confidence: 99%

“…The high affinity association between purified Hsp90 and the 20 S proteasome (K d Ͻ 100 nM), in conjunction with the routine presence of Hsp90 in purified preparations of the 20 S proteasome, suggests a possible functional involvement in modulating protein degradation (7,21,23,(32)(33)(34). Indeed, functional inhibitors of Hsp90 modulate the rates of protein degradation and inhibit the activity of the proteasome in cellular assays (21,25,28,35).…”

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confidence: 99%

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Hsp90 Enhances Degradation of Oxidized Calmodulin by the 20 S Proteasome

Whittier

Xiong

Rechsteiner

et al. 2004

Journal of Biological Chemistry

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The 20 S proteasome has been suggested to play a critical role in mediating the degradation of abnormal proteins under conditions of oxidative stress and has been found in tight association with the molecular chaperone Hsp90. To elucidate the role of Hsp90 in promoting the degradation of oxidized calmodulin (CaM ox ), we have purified red blood cell 20 S proteasomes free of Hsp90 and assessed their ability to degrade CaM ox in the absence or presence of Hsp90. Purified 20 S proteasome does not degrade CaM ox unless Hsp90 is added. CaM ox degradation is sensitive to both proteasome and Hsp90-specific inhibitors and is further enhanced in the presence of 2 mM ATP. Irrespective of the presence of Hsp90, we find that unoxidized CaM is not significantly degraded. Direct binding measurements demonstrate that Hsp90 selectively associates with CaM ox ; essentially no binding is observed between Hsp90 and unoxidized CaM. These results indicate that Hsp90 in association with the 20 S proteasome can selectively associate with oxidized and partially unfolded CaM to promote degradation by the proteasome.

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Interaction of Hsp90 with 20S proteasome: Thermodynamic and kinetic characterization

Cited by 35 publications

References 38 publications

Changes in Select Redox Proteins of the Retinal Pigment Epithelium in Age-related Macular Degeneration

Changes in Select Redox Proteins of the Retinal Pigment Epithelium in Age-related Macular Degeneration

HSP90 interacts with RAR1 and SGT1 and is essential for RPS2-mediated disease resistance in Arabidopsis

Hsp90 Enhances Degradation of Oxidized Calmodulin by the 20 S Proteasome

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