Biomolecules

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4 pages, 190 KiB

Open AccessEditorial

An Editorial on the Special Issue ‘Hsp90 Structure, Mechanism and Disease’

by Chrisostomos Prodromou

Biomolecules 2023, 13(3), 547; https://doi.org/10.3390/biom13030547 - 17 Mar 2023

Viewed by 1315

Abstract

Hsp90 is known for its role in the activation of an eclectic set of regulatory and signal transduction proteins [...] Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

Research

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25 pages, 5386 KiB

Open AccessArticle

Recognition of BRAF by CDC37 and Re-Evaluation of the Activation Mechanism for the Class 2 BRAF-L597R Mutant

by Dennis M. Bjorklund, R. Marc L. Morgan, Jasmeen Oberoi, Katie L. I. M. Day, Panagiota A. Galliou and Chrisostomos Prodromou

Biomolecules 2022, 12(7), 905; https://doi.org/10.3390/biom12070905 - 28 Jun 2022

Cited by 3 | Viewed by 2596

Abstract

The kinome specific co-chaperone, CDC37 (cell division cycle 37), is responsible for delivering BRAF (B-Rapidly Accelerated Fibrosarcoma) to the Hsp90 (heat shock protein 90) complex, where it is then translocated to the RAS (protooncogene product p21) complex at the plasma membrane for RAS [...] Read more.

The kinome specific co-chaperone, CDC37 (cell division cycle 37), is responsible for delivering BRAF (B-Rapidly Accelerated Fibrosarcoma) to the Hsp90 (heat shock protein 90) complex, where it is then translocated to the RAS (protooncogene product p21) complex at the plasma membrane for RAS mediated dimerization and subsequent activation. We identify a bipartite interaction between CDC37 and BRAF and delimitate the essential structural elements of CDC37 involved in BRAF recognition. We find an extended and conserved CDC37 motif, ²⁰HPNID---SL--W³¹, responsible for recognizing the C-lobe of BRAF kinase domain, while the c-terminal domain of CDC37 is responsible for the second of the bipartite interaction with BRAF. We show that dimerization of BRAF, independent of nucleotide binding, can act as a potent signal that prevents CDC37 recognition and discuss the implications of mutations in BRAF and the consequences on signaling in a clinical setting, particularly for class 2 BRAF mutations. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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13 pages, 2797 KiB

Open AccessArticle

The APE2 Exonuclease Is a Client of the Hsp70–Hsp90 Axis in Yeast and Mammalian Cells

by Siddhi Omkar, Tasaduq H. Wani, Bo Zheng, Megan M. Mitchem and Andrew W. Truman

Biomolecules 2022, 12(7), 864; https://doi.org/10.3390/biom12070864 - 21 Jun 2022

Cited by 3 | Viewed by 2813

Abstract

Molecular chaperones such as Hsp70 and Hsp90 help fold and activate proteins in important signal transduction pathways that include DNA damage response (DDR). Previous studies have suggested that the levels of the mammalian APE2 exonuclease, a protein critical for DNA repair, may be [...] Read more.

Molecular chaperones such as Hsp70 and Hsp90 help fold and activate proteins in important signal transduction pathways that include DNA damage response (DDR). Previous studies have suggested that the levels of the mammalian APE2 exonuclease, a protein critical for DNA repair, may be dependent on chaperone activity. In this study, we demonstrate that the budding yeast Apn2 exonuclease interacts with molecular chaperones Ssa1 and Hsp82 and the co-chaperone Ydj1. Although Apn2 does not display a binding preference for any specific cytosolic Hsp70 or Hsp90 paralog, Ssa1 is unable to support Apn2 stability when present as the sole Ssa in the cell. Demonstrating conservation of this mechanism, the exonuclease APE2 also binds to Hsp70 and Hsp90 in mammalian cells. Inhibition of chaperone function via specific small molecule inhibitors results in a rapid loss of APE2 in a range of cancer cell lines. Taken together, these data identify APE2 and Apn2 as clients of the chaperone system in yeast and mammalian cells and suggest that chaperone inhibition may form the basis of novel anticancer therapies that target APE2-mediated processes. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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24 pages, 4142 KiB

Open AccessEditor’s ChoiceArticle

Non-Equilibrium Protein Folding and Activation by ATP-Driven Chaperones

by Huafeng Xu

Biomolecules 2022, 12(6), 832; https://doi.org/10.3390/biom12060832 - 15 Jun 2022

Cited by 3 | Viewed by 3965

Abstract

Recent experimental studies suggest that ATP-driven molecular chaperones can stabilize protein substrates in their native structures out of thermal equilibrium. The mechanism of such non-equilibrium protein folding is an open question. Based on available structural and biochemical evidence, I propose here a unifying [...] Read more.

Recent experimental studies suggest that ATP-driven molecular chaperones can stabilize protein substrates in their native structures out of thermal equilibrium. The mechanism of such non-equilibrium protein folding is an open question. Based on available structural and biochemical evidence, I propose here a unifying principle that underlies the conversion of chemical energy from ATP hydrolysis to the conformational free energy associated with protein folding and activation. I demonstrate that non-equilibrium folding requires the chaperones to break at least one of four symmetry conditions. The Hsp70 and Hsp90 chaperones each break a different subset of these symmetries and thus they use different mechanisms for non-equilibrium protein folding. I derive an upper bound on the non-equilibrium elevation of the native concentration, which implies that non-equilibrium folding only occurs in slow-folding proteins that adopt an unstable intermediate conformation in binding to ATP-driven chaperones. Contrary to the long-held view of Anfinsen’s hypothesis that proteins fold to their conformational free energy minima, my results predict that some proteins may fold into thermodynamically unstable native structures with the assistance of ATP-driven chaperones, and that the native structures of some chaperone-dependent proteins may be shaped by their chaperone-mediated folding pathways. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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Review

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14 pages, 870 KiB

Open AccessEditor’s ChoiceReview

Organismal Roles of Hsp90

by Patricija van Oosten-Hawle

Biomolecules 2023, 13(2), 251; https://doi.org/10.3390/biom13020251 - 29 Jan 2023

Cited by 8 | Viewed by 2836

Abstract

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction. As a regulator of cellular signaling processes, it is vital for the maintenance of cellular proteostasis and adaptation [...] Read more.

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction. As a regulator of cellular signaling processes, it is vital for the maintenance of cellular proteostasis and adaptation to environmental stresses. Emerging research shows that Hsp90 function in an organism goes well beyond intracellular proteostasis. In metazoans, Hsp90, as an environmentally responsive chaperone, is involved in inter-tissue stress signaling responses that coordinate and safeguard cell nonautonomous proteostasis and organismal health. In this way, Hsp90 has the capacity to influence evolution and aging, and effect behavioral responses to facilitate tissue-defense systems that ensure organismal survival. In this review, I summarize the literature on the organismal roles of Hsp90 uncovered in multicellular organisms, from plants to invertebrates and mammals. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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22 pages, 819 KiB

Open AccessEditor’s ChoiceReview

Cytosolic Hsp90 Isoform-Specific Functions and Clinical Significance

by Samarpan Maiti and Didier Picard

Biomolecules 2022, 12(9), 1166; https://doi.org/10.3390/biom12091166 - 23 Aug 2022

Cited by 31 | Viewed by 4668

Abstract

The heat shock protein 90 (Hsp90) is a molecular chaperone and a key regulator of proteostasis under both physiological and stress conditions. In mammals, there are two cytosolic Hsp90 isoforms: Hsp90α and Hsp90β. These two isoforms are 85% identical and encoded by two [...] Read more.

The heat shock protein 90 (Hsp90) is a molecular chaperone and a key regulator of proteostasis under both physiological and stress conditions. In mammals, there are two cytosolic Hsp90 isoforms: Hsp90α and Hsp90β. These two isoforms are 85% identical and encoded by two different genes. Hsp90β is constitutively expressed and essential for early mouse development, while Hsp90α is stress-inducible and not necessary for survivability. These two isoforms are known to have largely overlapping functions and to interact with a large fraction of the proteome. To what extent there are isoform-specific functions at the protein level has only relatively recently begun to emerge. There are studies indicating that one isoform is more involved in the functionality of a specific tissue or cell type. Moreover, in many diseases, functionally altered cells appear to be more dependent on one particular isoform. This leaves space for designing therapeutic strategies in an isoform-specific way, which may overcome the unfavorable outcome of pan-Hsp90 inhibition encountered in previous clinical trials. For this to succeed, isoform-specific functions must be understood in more detail. In this review, we summarize the available information on isoform-specific functions of mammalian Hsp90 and connect it to possible clinical applications. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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11 pages, 1637 KiB

Open AccessReview

Regulation of Protein Transport Pathways by the Cytosolic Hsp90s

by Anna G. Mankovich and Brian C. Freeman

Biomolecules 2022, 12(8), 1077; https://doi.org/10.3390/biom12081077 - 5 Aug 2022

Cited by 6 | Viewed by 2871

Abstract

The highly conserved molecular chaperone heat shock protein 90 (Hsp90) is well-known for maintaining metastable proteins and mediating various aspects of intracellular protein dynamics. Intriguingly, high-throughput interactome studies suggest that Hsp90 is associated with a variety of other pathways. Here, we will highlight [...] Read more.

The highly conserved molecular chaperone heat shock protein 90 (Hsp90) is well-known for maintaining metastable proteins and mediating various aspects of intracellular protein dynamics. Intriguingly, high-throughput interactome studies suggest that Hsp90 is associated with a variety of other pathways. Here, we will highlight the potential impact of Hsp90 in protein transport. Currently, a limited number of studies have defined a few mechanistic contributions of Hsp90 to protein transport, yet the relevance of hundreds of additional connections between Hsp90 and factors known to aide this process remains unresolved. These interactors broadly support transport pathways including endocytic and exocytic vesicular transport, the transfer of polypeptides across membranes, or unconventional protein secretion. In resolving how Hsp90 contributes to the protein transport process, new therapeutic targets will likely be obtained for the treatment of numerous human health issues, including bacterial infection, cancer metastasis, and neurodegeneration. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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29 pages, 2784 KiB

Open AccessReview

The Role of Hsp90-R2TP in Macromolecular Complex Assembly and Stabilization

by Jeffrey Lynham and Walid A. Houry

Biomolecules 2022, 12(8), 1045; https://doi.org/10.3390/biom12081045 - 28 Jul 2022

Cited by 14 | Viewed by 4188

Abstract

Hsp90 is a ubiquitous molecular chaperone involved in many cell signaling pathways, and its interactions with specific chaperones and cochaperones determines which client proteins to fold. Hsp90 has been shown to be involved in the promotion and maintenance of proper protein complex assembly [...] Read more.

Hsp90 is a ubiquitous molecular chaperone involved in many cell signaling pathways, and its interactions with specific chaperones and cochaperones determines which client proteins to fold. Hsp90 has been shown to be involved in the promotion and maintenance of proper protein complex assembly either alone or in association with other chaperones such as the R2TP chaperone complex. Hsp90-R2TP acts through several mechanisms, such as by controlling the transcription of protein complex subunits, stabilizing protein subcomplexes before their incorporation into the entire complex, and by recruiting adaptors that facilitate complex assembly. Despite its many roles in protein complex assembly, detailed mechanisms of how Hsp90-R2TP assembles protein complexes have yet to be determined, with most findings restricted to proteomic analyses and in vitro interactions. This review will discuss our current understanding of the function of Hsp90-R2TP in the assembly, stabilization, and activity of the following seven classes of protein complexes: L7Ae snoRNPs, spliceosome snRNPs, RNA polymerases, PIKKs, MRN, TSC, and axonemal dynein arms. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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10 pages, 916 KiB

Open AccessReview

UCS Chaperone Folding of the Myosin Head: A Function That Evolved before Animals and Fungi Diverged from a Common Ancestor More than a Billion Years Ago

by Peter William Piper, Julia Elizabeth Scott and Stefan Heber Millson

Biomolecules 2022, 12(8), 1028; https://doi.org/10.3390/biom12081028 - 26 Jul 2022

Cited by 1 | Viewed by 2223

Abstract

The folding of the myosin head often requires a UCS (Unc45, Cro1, She4) domain-containing chaperone. Worms, flies, and fungi have just a single UCS protein. Vertebrates have two; one (Unc45A) which functions primarily in non-muscle cells and another (Unc45B) that is essential for [...] Read more.

The folding of the myosin head often requires a UCS (Unc45, Cro1, She4) domain-containing chaperone. Worms, flies, and fungi have just a single UCS protein. Vertebrates have two; one (Unc45A) which functions primarily in non-muscle cells and another (Unc45B) that is essential for establishing and maintaining the contractile apparatus of cardiac and skeletal muscles. The domain structure of these proteins suggests that the UCS function evolved before animals and fungi diverged from a common ancestor more than a billion years ago. UCS proteins of metazoans and apicomplexan parasites possess a tetratricopeptide repeat (TPR), a domain for direct binding of the Hsp70/Hsp90 chaperones. This, however, is absent in the UCS proteins of fungi and largely nonessential for the UCS protein function in Caenorhabditis elegans and zebrafish. The latter part of this review focusses on the TPR-deficient UCS proteins of fungi. While these are reasonably well studied in yeasts, there is little precise information as to how they might engage in interactions with the Hsp70/Hsp90 chaperones or might assist in myosin operations during the hyphal growth of filamentous fungi. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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16 pages, 1548 KiB

Open AccessReview

Hsp90 and Associated Co-Chaperones of the Malaria Parasite

by Tanima Dutta, Harpreet Singh, Adrienne L Edkins and Gregory L Blatch

Biomolecules 2022, 12(8), 1018; https://doi.org/10.3390/biom12081018 - 22 Jul 2022

Cited by 11 | Viewed by 3870

Abstract

Heat shock protein 90 (Hsp90) is one of the major guardians of cellular protein homeostasis, through its specialized molecular chaperone properties. While Hsp90 has been extensively studied in many prokaryotic and higher eukaryotic model organisms, its structural, functional, and biological properties in parasitic [...] Read more.

Heat shock protein 90 (Hsp90) is one of the major guardians of cellular protein homeostasis, through its specialized molecular chaperone properties. While Hsp90 has been extensively studied in many prokaryotic and higher eukaryotic model organisms, its structural, functional, and biological properties in parasitic protozoans are less well defined. Hsp90 collaborates with a wide range of co-chaperones that fine-tune its protein folding pathway. Co-chaperones play many roles in the regulation of Hsp90, including selective targeting of client proteins, and the modulation of its ATPase activity, conformational changes, and post-translational modifications. Plasmodium falciparum is responsible for the most lethal form of human malaria. The survival of the malaria parasite inside the host and the vector depends on the action of molecular chaperones. The major cytosolic P. falciparum Hsp90 (PfHsp90) is known to play an essential role in the development of the parasite, particularly during the intra-erythrocytic stage in the human host. Although PfHsp90 shares significant sequence and structural similarity with human Hsp90, it has several major structural and functional differences. Furthermore, its co-chaperone network appears to be substantially different to that of the human host, with the potential absence of a key homolog. Indeed, PfHsp90 and its interface with co-chaperones represent potential drug targets for antimalarial drug discovery. In this review, we critically summarize the current understanding of the properties of Hsp90, and the associated co-chaperones of the malaria parasite. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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20 pages, 1111 KiB

Open AccessReview

The Role of Hsp90 in Retinal Proteostasis and Disease

by Kalliopi Ziaka and Jacqueline van der Spuy

Biomolecules 2022, 12(7), 978; https://doi.org/10.3390/biom12070978 - 12 Jul 2022

Cited by 4 | Viewed by 3059

Abstract

Photoreceptors are sensitive neuronal cells with great metabolic demands, as they are responsible for carrying out visual phototransduction, a complex and multistep process that requires the exquisite coordination of a large number of signalling protein components. Therefore, the viability of photoreceptors relies on [...] Read more.

Photoreceptors are sensitive neuronal cells with great metabolic demands, as they are responsible for carrying out visual phototransduction, a complex and multistep process that requires the exquisite coordination of a large number of signalling protein components. Therefore, the viability of photoreceptors relies on mechanisms that ensure a well-balanced and functional proteome that maintains the protein homeostasis, or proteostasis, of the cell. This review explores how the different isoforms of Hsp90, including the cytosolic Hsp90α/β, the mitochondrial TRAP1, and the ER-specific GRP94, are involved in the different proteostatic mechanisms of photoreceptors, and elaborates on Hsp90 function when retinal homeostasis is disturbed. In addition, several studies have shown that chemical manipulation of Hsp90 has significant consequences, both in healthy and degenerating retinae, and this can be partially attributed to the fact that Hsp90 interacts with important photoreceptor-associated client proteins. Here, the interaction of Hsp90 with the retina-specific client proteins PDE6 and GRK1 will be further discussed, providing additional insights for the role of Hsp90 in retinal disease. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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21 pages, 1356 KiB

Open AccessEditor’s ChoiceReview

Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer

by Sarah J. Backe, Rebecca A. Sager, Katherine A. Meluni, Mark R. Woodford, Dimitra Bourboulia and Mehdi Mollapour

Biomolecules 2022, 12(7), 928; https://doi.org/10.3390/biom12070928 - 1 Jul 2022

Cited by 5 | Viewed by 3514

Abstract

Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and [...] Read more.

Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and Tsc1 has broadened the spectrum of Hsp90 regulators. These new co-chaperones mediate the stability of critical tumor suppressors FLCN and Tsc2 as well as the various classes of Hsp90 kinase and non-kinase clients. Many early observations of the roles of FNIP1, FNIP2, and Tsc1 suggested functions independent of FLCN and Tsc2 but have not been fully delineated. Given the broad cellular impact of Hsp90-dependent signaling, it is possible to explain the cellular activities of these new co-chaperones by their influence on Hsp90 function. Here, we review the literature on FNIP1, FNIP2, and Tsc1 as co-chaperones and discuss the potential downstream impact of this regulation on normal cellular function and in human diseases. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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20 pages, 1792 KiB

Open AccessReview

Extracellular Heat Shock Protein-90 (eHsp90): Everything You Need to Know

by Daniel Jay, Yongzhang Luo and Wei Li

Biomolecules 2022, 12(7), 911; https://doi.org/10.3390/biom12070911 - 29 Jun 2022

Cited by 18 | Viewed by 5104

Abstract

“Extracellular” Heat Shock Protein-90 (Hsp90) was initially reported in the 1970s but was not formally recognized until 2008 at the 4th International Conference on The Hsp90 Chaperone Machine (Monastery Seeon, Germany). Studies presented under the topic of “extracellular Hsp90 (eHsp90)” at the conference [...] Read more.

“Extracellular” Heat Shock Protein-90 (Hsp90) was initially reported in the 1970s but was not formally recognized until 2008 at the 4th International Conference on The Hsp90 Chaperone Machine (Monastery Seeon, Germany). Studies presented under the topic of “extracellular Hsp90 (eHsp90)” at the conference provided direct evidence for eHsp90’s involvement in cancer invasion and skin wound healing. Over the past 15 years, studies have focused on the secretion, action, biological function, therapeutic targeting, preclinical evaluations, and clinical utility of eHsp90 using wound healing, tissue fibrosis, and tumour models both in vitro and in vivo. eHsp90 has emerged as a critical stress-responding molecule targeting each of the pathophysiological conditions. Despite the studies, our current understanding of several fundamental questions remains little beyond speculation. Does eHsp90 indeed originate from purposeful live cell secretion or rather from accidental dead cell leakage? Why did evolution create an intracellular chaperone that also functions as a secreted factor with reported extracellular duties that might be (easily) fulfilled by conventional secreted molecules? Is eHsp90 a safer and more optimal drug target than intracellular Hsp90 chaperone? In this review, we summarize how much we have learned about eHsp90, provide our conceptual views of the findings, and make recommendations on the future studies of eHsp90 for clinical relevance. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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13 pages, 1806 KiB

Open AccessEditor’s ChoiceReview

The Mitochondrial HSP90 Paralog TRAP1: Structural Dynamics, Interactome, Role in Metabolic Regulation, and Inhibitors

by Abhinav Joshi, Takeshi Ito, Didier Picard and Len Neckers

Biomolecules 2022, 12(7), 880; https://doi.org/10.3390/biom12070880 - 24 Jun 2022

Cited by 15 | Viewed by 4179

Abstract

The HSP90 paralog TRAP1 was discovered more than 20 years ago; yet, a detailed understanding of the function of this mitochondrial molecular chaperone remains elusive. The dispensable nature of TRAP1 in vitro and in vivo further complicates an understanding of its role in [...] Read more.

The HSP90 paralog TRAP1 was discovered more than 20 years ago; yet, a detailed understanding of the function of this mitochondrial molecular chaperone remains elusive. The dispensable nature of TRAP1 in vitro and in vivo further complicates an understanding of its role in mitochondrial biology. TRAP1 is more homologous to the bacterial HSP90, HtpG, than to eukaryotic HSP90. Lacking co-chaperones, the unique structural features of TRAP1 likely regulate its temperature-sensitive ATPase activity and shed light on the alternative mechanisms driving the chaperone’s nucleotide-dependent cycle in a defined environment whose physiological temperature approaches 50 °C. TRAP1 appears to be an important bioregulator of mitochondrial respiration, mediating the balance between oxidative phosphorylation and glycolysis, while at the same time promoting mitochondrial homeostasis and displaying cytoprotective activity. Inactivation/loss of TRAP1 has been observed in several neurodegenerative diseases while TRAP1 expression is reported to be elevated in multiple cancers and, as with HSP90, evidence of addiction to TRAP1 has been observed. In this review, we summarize what is currently known about this unique HSP90 paralog and why a better understanding of TRAP1 structure, function, and regulation is likely to enhance our understanding of the mechanistic basis of mitochondrial homeostasis. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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19 pages, 2670 KiB

Open AccessEditor’s ChoiceReview

TRAP1 Chaperones the Metabolic Switch in Cancer

by Laura A. Wengert, Sarah J. Backe, Dimitra Bourboulia, Mehdi Mollapour and Mark R. Woodford

Biomolecules 2022, 12(6), 786; https://doi.org/10.3390/biom12060786 - 4 Jun 2022

Cited by 20 | Viewed by 4596

Abstract

Mitochondrial function is dependent on molecular chaperones, primarily due to their necessity in the formation of respiratory complexes and clearance of misfolded proteins. Heat shock proteins (Hsps) are a subset of molecular chaperones that function in all subcellular compartments, both constitutively and in [...] Read more.

Mitochondrial function is dependent on molecular chaperones, primarily due to their necessity in the formation of respiratory complexes and clearance of misfolded proteins. Heat shock proteins (Hsps) are a subset of molecular chaperones that function in all subcellular compartments, both constitutively and in response to stress. The Hsp90 chaperone TNF-receptor-associated protein-1 (TRAP1) is primarily localized to the mitochondria and controls both cellular metabolic reprogramming and mitochondrial apoptosis. TRAP1 upregulation facilitates the growth and progression of many cancers by promoting glycolytic metabolism and antagonizing the mitochondrial permeability transition that precedes multiple cell death pathways. TRAP1 attenuation induces apoptosis in cellular models of cancer, identifying TRAP1 as a potential therapeutic target in cancer. Similar to cytosolic Hsp90 proteins, TRAP1 is also subject to post-translational modifications (PTM) that regulate its function and mediate its impact on downstream effectors, or ‘clients’. However, few effectors have been identified to date. Here, we will discuss the consequence of TRAP1 deregulation in cancer and the impact of post-translational modification on the known functions of TRAP1. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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23 pages, 5768 KiB

Open AccessEditor’s ChoiceReview

Advances towards Understanding the Mechanism of Action of the Hsp90 Complex

by Chrisostomos Prodromou and Dennis M. Bjorklund

Biomolecules 2022, 12(5), 600; https://doi.org/10.3390/biom12050600 - 19 Apr 2022

Cited by 27 | Viewed by 4816

Abstract

Hsp90 (Heat Shock Protein 90) is an ATP (Adenosine triphosphate) molecular chaperone responsible for the activation and maturation of client proteins. The mechanism by which Hsp90 achieves such activation, involving structurally diverse client proteins, has remained enigmatic. However, recent advances using structural techniques, [...] Read more.

Hsp90 (Heat Shock Protein 90) is an ATP (Adenosine triphosphate) molecular chaperone responsible for the activation and maturation of client proteins. The mechanism by which Hsp90 achieves such activation, involving structurally diverse client proteins, has remained enigmatic. However, recent advances using structural techniques, together with advances in biochemical studies, have not only defined the chaperone cycle but have shed light on its mechanism of action. Hsp90 hydrolysis of ATP by each protomer may not be simultaneous and may be dependent on the specific client protein and co-chaperone complex involved. Surprisingly, Hsp90 appears to remodel client proteins, acting as a means by which the structure of the client protein is modified to allow its subsequent refolding to an active state, in the case of kinases, or by making the client protein competent for hormone binding, as in the case of the GR (glucocorticoid receptor). This review looks at selected examples of client proteins, such as CDK4 (cyclin-dependent kinase 4) and GR, which are activated according to the so-called ‘remodelling hypothesis’ for their activation. A detailed description of these activation mechanisms is paramount to understanding how Hsp90-associated diseases develop. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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