Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy

Marozkina, Nadzeya; Yemen, Sean; Borowitz, Molly; Liu, Lei; Plapp, Melissa; Sun, Fei; Islam, Rafique; Erdmann-Gilmore, Petra; Townsend, R. Reid; Lichti, Cheryl F.; Mantri, Sneha; Clapp, Phillip W.; Randell, Scott H.; Gaston, Benjamin; Zaman, Khalequz

doi:10.1073/pnas.0909128107

Cited by 65 publications

(85 citation statements)

References 43 publications

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“…Different categories of chaperone operate for TMPs, and the chaperone activity that is best characterized is of those located in the lumen of the ER (Braakman and Bulleid, 2011). However, cytosolic chaperones of the Hsp90, Hsp70 and Hsp40 families have been shown to assist in the folding of several TMPs by interacting with their cytosolic moiety and eventually causing different effects defined by the properties of each client protein (Beckmann et al, 1990;Marozkina et al, 2010;Mayer and Bukau, 2005;Peters et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

The cytosolic chaperone α-Crystallin B rescues appropriate folding and compartmentalization of misfolded multispan transmembrane proteins

D’Agostino¹,

Lemma²,

Chesi³

et al. 2013

Journal of Cell Science

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SummaryThe a-crystallin B chain (CRYAB or HspB5) is a cytosolic chaperone belonging to the small heat shock protein family, which is known to help in the folding of cytosolic proteins. Here we show that CRYAB binds the mutant form of at least two multispan transmembrane proteins (TMPs), exerting an anti-aggregation activity. It rescues the folding of mutant Frizzled4, which is responsible for a rare autosomal dominant form of familial exudative vitreoretinopathy (Fz4-FEVR), and the mutant ATP7B Cu transporter (ATP7B-H1069Q) associated with a common form of Wilson's disease. In the case of Fz4-FEVR, CRYAB prevents the formation of inter-chain disulfide bridges between the lumenal ectodomains of the aggregated mutant chains, which enables correct folding and promotes appropriate compartmentalization on the plasma membrane. ATP7B-H1069Q, with help from CRYAB, folds into the proper conformation, moves to the Golgi complex, and responds to copper overload in the same manner as wild-type ATP7B. These findings strongly suggest that CRYAB plays a pivotal role, previously undetected, in the folding of multispan TMPs and, from the cytosol, is able to orchestrate folding events that take place in the lumen of the ER. Our results contribute to the explanation of the complex scenario behind multispan TMP folding; additionally, they serve to expose interesting avenues for novel therapeutic approaches.

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Section: Introductionmentioning

confidence: 99%

The cytosolic chaperone α-Crystallin B rescues appropriate folding and compartmentalization of misfolded multispan transmembrane proteins

D’Agostino¹,

Lemma²,

Chesi³

et al. 2013

Journal of Cell Science

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“…For instance, in selected cases these co-chaperones have been linked to quality control of the client proteins, as shown for the mutant cystic brosis transmembrane conductance regulator (CFTR). 48 Still, signicant knowledge gaps have to be acknowledged. There are likely many more co-chaperones than those described here.…”

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confidence: 99%

Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapy

et al. 2013

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In this review recent progress in the development of heat shock proteins (Hsp90) in oncogenesis is illuminated. Particular emphasis is put on inhibitors such as geldanamycin and analogues that serve as a natural product show case. Hsp90 has emerged as an important target in cancer therapy and/or against pathogenic cells which elicit abnormal Hsp patterns. Competition for ATP by geldanamycin and related compounds abrogate the chaperone function of Hsp90. In this context, this account pursues three topics in detail: a) Hsp90 and its biochemistry, b) Hsp90 and its role in oncogenesis and c) strategies to create compound libraries of structurally complex inhibitors like geldanamycin on which SAR studies and the development of drugs that are currently in different stages of clinical testing rely.

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“…The leading cause of cystic fibrosis is the presence of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A variant of CFTR harbouring a phenylalanine deletion (CFTR ΔF508) has been shown to interact directly with Hop (Marozkina et al 2010). Hop captures CFTR ΔF508 and prevents its maturation, thereby blocking its function.…”

Section: Developmental and Protein Folding Disordersmentioning

confidence: 99%

Hsp70/Hsp90 Organising Protein (Hop): Beyond Interactions with Chaperones and Prion Proteins

Baindur-Hudson

Edkins

Blatch

2014

Subcellular Biochemistry

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The Hsp70/Hsp90 organising protein (Hop), also known as stress-inducible protein 1 (STI1), has received considerable attention for diverse cellular functions in both healthy and diseased states. There is extensive evidence that intracellular Hop is a co-chaperone of the major chaperones Hsp70 and Hsp90, playing an important role in the productive folding of Hsp90 client proteins. Consequently, Hop is implicated in a number of key signalling pathways, including aberrant pathways leading to cancer. However, Hop is also secreted and it is now well established that Hop also serves as a receptor for the prion protein, PrP(C). The intracellular and extracellular forms of Hop most likely represent two different isoforms, although the molecular determinants of these divergent functions are yet to be identified. There is also a growing body of research that reports the involvement of Hop in cellular activities that appear independent of either chaperones or PrP(C). While Hop has been shown to have various cellular functions, its biological function remains elusive. However, recent knockout studies in mammals suggest that Hop has an important role in embryonic development. This review provides a critical overview of the latest molecular, cellular and biological research on Hop, critically evaluating its function in healthy systems and how this function is adapted in diseases states.

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Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy

Cited by 65 publications

References 43 publications

The cytosolic chaperone α-Crystallin B rescues appropriate folding and compartmentalization of misfolded multispan transmembrane proteins

The cytosolic chaperone α-Crystallin B rescues appropriate folding and compartmentalization of misfolded multispan transmembrane proteins

Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapy

Hsp70/Hsp90 Organising Protein (Hop): Beyond Interactions with Chaperones and Prion Proteins

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