Hsp90 chaperones hemoglobin maturation in erythroid and nonerythroid cells

Ghosh, Arnab; Garee, Greer; Sweeny, Elizabeth A.; Nakamura, Yukio; Stuehr, Dennis J.

doi:10.1073/pnas.1717993115

Cited by 43 publications

(73 citation statements)

References 46 publications

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“…Our study is the first to probe the mechanisms of Mb maturation during this process and reveals that the hsp90/ cochaperone machinery associates with apo-Mb to ultimately drive heme insertion, which is an essential step for generating mature and functional Mb. Thus, Mb joins a growing list of hemeproteins whose heme insertion is hsp90-dependent, which at present includes the NO synthases (25), sGCb1 (26), and Hb-b and g (27).…”

Section: Discussionmentioning

confidence: 99%

“…Heat shock protein (hsp) 90 is a molecular chaperone that regulates the cellular stress response by maintaining the conformation, stability, and function of numerous client proteins (16)(17)(18)(19). Hsp90 also assists in the ligand binding of diverse protein clients, including steroid-binding proteins (20,21), the arylhydrocarbon receptor (22), kinases (23,24), the hemeproteins NO synthase (25), soluble guanylyl cyclase (sGC) b subunit (26), and hemoglobins (Hbs) b and g (27). Several lines of evidence also suggest important roles for hsp90 in muscle physiology, including myofibril assembly (28,29), muscle fiber lineages (30), and myogenic differentiation (31).…”

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confidence: 99%

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Myoglobin maturation is driven by the hsp90 chaperone machinery and by soluble guanylyl cyclase

et al. 2019

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Myoglobin (Mb) maturation involves heme incorporation as a final step. We investigated a role for heat shock protein (hsp) 90 in Mb maturation in C2C12 skeletal muscle myoblasts and cell lines. We found the following: 1) Hsp90 directly interacts preferentially with heme‐free Mb both in purified form and in cells. 2) Hsp90 drives heme insertion into apoprotein‐Mb in an ATP‐dependent process. 3) During differentiation of C2C12 myoblasts into myotubes, the apo‐Mb‐hsp90 complex associates with 5 cell cochaperons, Hsp70, activator of hsp90 ATPase protein 1 (Aha1), alanyl‐tRNA synthetase domain containing 1 (Aarsd1), cell division cycle 37 (Cdc37), and stress induced phosphoprotein 1 (STIP1) in a pattern that is consistent with their enabling Mb maturation. 4) Mb heme insertion was significantly increased in cells that had a functional soluble guanylyl cyclase (sGC)‐cGMP signaling pathway and was diminished upon small interfering RNA knockdown of sGCβ1 or upon overexpression of a phosphodiesterase to prevent cGMP buildup. Together, our findings suggest that hsp90 works in concert with cochaperons (Hsp70, Aha1, Aarsd1, STIP1, and Cdc37) and an active sGC‐cGMP signaling pathway to promote heme insertion into immature apo‐Mb, and thus generate functional Mb during muscle myotube formation. This fills gaps in our understanding and suggests new ways to potentially control these processes.—Ghosh, A., Dai, Y., Biswas, P., Stuehr, D. J. Myoglobin maturation is driven by the hsp90 chaperone machinery and by soluble guanylyl cyclase. FASEB J. 33, 9885–9896 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Myoglobin maturation is driven by the hsp90 chaperone machinery and by soluble guanylyl cyclase

et al. 2019

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“…Yet, in a third category Hsp90 action favors ligand binding as it does in SHRs (Pratt and Dittmar 1998;Kirschke et al 2014;Lorenz et al 2014). Also, the heme insertion into βand γ-globins is dependent on Hsp90 (Ghosh et al 2018). Furthermore, Hsp90 also promotes heme insertion into soluble guanylyl cyclase and inducible nitric oxide (NO) synthase (Ghosh et al 2011;Ghosh and Stuehr 2012).…”

Section: How Hsp90 Recognizes and Folds Clientsmentioning

confidence: 99%

Structure, Function, and Regulation of the Hsp90 Machinery

Biebl

Büchner

2019

Cold Spring Harb Perspect Biol

211

192

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“…Besides sGC␤, it is intriguing to speculate that heme insertion into other known HSP90 clients, such as globins (33) and NO synthases (34), may also involve a direct complex formation with HSP90. These clients do not contain PAS domains, so their interactions with HSP90 would need to involve distinct protein regions.…”

Section: Possible Mechanism Of Hsp90 Action In Heme Insertionmentioning

confidence: 99%

Heat shock protein 90 regulates soluble guanylyl cyclase maturation by a dual mechanism

Dai

Schlanger

Haque

et al. 2019

Journal of Biological Chemistry

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Edited by Ruma Banerjee The enzyme soluble guanylyl cyclase (sGC) is a heterodimer composed of an ␣ subunit and a heme-containing ␤ subunit. It participates in signaling by generating cGMP in response to nitric oxide (NO). Heme insertion into the ␤1 subunit of sGC (sGC␤) is critical for function, and heat shock protein 90 (HSP90) associates with heme-free sGC␤ (apo-sGC␤) to drive its heme insertion. Here, we tested the accuracy and relevance of a modeled apo-sGC␤-HSP90 complex by constructing sGC␤ variants predicted to have an impaired interaction with HSP90. Using site-directed mutagenesis, purified recombinant proteins, mammalian cell expression, and fluorescence approaches, we found that (i) three regions in apo-sGC␤ predicted by the model mediate direct complex formation with HSP90 both in vitro and in mammalian cells; (ii) such HSP90 complex formation directly correlates with the extent of heme insertion into apo-sGC␤ and with cyclase activity; and (iii) apo-sGC␤ mutants possessing an HSP90-binding defect instead bind to sGC␣ in cells and form inactive, heme-free sGC heterodimers. Our findings uncover the molecular features of the cellular apo-sGC␤-HSP90 complex and reveal its dual importance in enabling heme insertion while preventing inactive heterodimer formation during sGC maturation.

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Hsp90 chaperones hemoglobin maturation in erythroid and nonerythroid cells

Cited by 43 publications

References 46 publications

Myoglobin maturation is driven by the hsp90 chaperone machinery and by soluble guanylyl cyclase

Myoglobin maturation is driven by the hsp90 chaperone machinery and by soluble guanylyl cyclase

Structure, Function, and Regulation of the Hsp90 Machinery

Heat shock protein 90 regulates soluble guanylyl cyclase maturation by a dual mechanism

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