Targeting the mitochondrial chaperone TRAP1: strategies and therapeutic perspectives

Serapian, Stefano A.; Sánchez-Martín, Carlos; Moroni, Elisabetta; Rasola, Andrea; Colombo, Giorgio

doi:10.1016/j.tips.2021.04.003

Cited by 23 publications

(17 citation statements)

References 67 publications

(93 reference statements)

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“…The chaperone Trap1 − is the mitochondrial member of the Hsp90 family. Occurring ubiquitously in healthy tissues of all complex organisms, it is, however, over- or underexpressed in cancers, depending on their types and grades. , As such, together with its homologues located in the cytosol and in the endoplasmic reticulum, this homodimeric (Figure ) protein has been attracting interest as a potential target for ortho- and allosteric anticancer drugs. ,, Trap1’s essential task is to bind a series of “client” proteins to oversee their folding and/or regulate mitochondrial functions, likely , assisted by “cochaperones” as is the case with its other homologues . This feat is achieved thanks to the chaperone’s fluxional nature, which makes it able to switch between a variety of very different conformations in delicate equilibrium among themselves (all amply documented). ,,,, …”

Section: Introductionmentioning

confidence: 99%

Atomistic Simulations of the Mechanisms of the Poorly Catalytic Mitochondrial Chaperone Trap1: Insights into the Effects of Structural Asymmetry on Reactivity

Serapian

Moroni²,

Ferraro³

et al. 2021

ACS Catal.

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The mitochondrial chaperone Trap1 is an ATPase protein that oversees the correct folding of client proteins and exhibits altered activity and/or expression levels in certain cancers. By inducing extensive structural rearrangements, ATP cleavage is essential for Trap1 to fulfill its task; at the same time, Trap1’s sluggish ATP turnover represents one of the control switches through which its conformational cycle and inter-residue cross-talk signals mediating it can be subtly tuned. Remarkably, hydrolysis requires Trap1 to adopt a distinctive asymmetric “closed” homodimeric conformation wherein the ATP bound to the “buckled” protomer (Buc) is preferentially cleaved, while hydrolysis in the “straight” protomer (Str) remains unfavored. However, molecular links between asymmetry and Trap1’s characteristic reactivity remain elusive, due to intrinsic mechanistic complexity and its protomers’ active site similarity. To address this issue, we herein report a detailed computational investigation of Trap1’s potential ATPase mechanisms. Through classical molecular dynamics (MD) simulations we monitor how frequently ATP and nucleophilic water Wat Nuc can attain reactive poses within Buc and Str. Semiempirical hybrid quantum mechanical–molecular mechanical (QM/MM) MD simulations coupled to umbrella sampling and benchmarked with density functional theory calculations are then used to sample reaction free energy barriers within each protomer for two possible hydrolytic pathways. Enzyme-assisted hydrolysis, featuring a metaphosphate-like transition state and a catalytic glutamate deprotonating Wat Nuc , is found to be favored in both protomers over substrate-assisted hydrolysis. However, we also find that Wat Nuc ’s sequestration by another water molecule Wat Tyr bound to a vicinal tyrosine is far rarer in Buc, proving that such a rare sequestration lowers reaction barriers for the enzyme-assisted pathway. We thus identify the (biologically significant) tyrosine as the main mediator favoring ATP hydrolysis in Buc over Str. Our improved model for Trap1 reactivity is experimentally and structurally consistent and should further aid in the development of selective modulators of the protein’s activities.

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Section: Introductionmentioning

confidence: 99%

Atomistic Simulations of the Mechanisms of the Poorly Catalytic Mitochondrial Chaperone Trap1: Insights into the Effects of Structural Asymmetry on Reactivity

Serapian

Moroni²,

Ferraro³

et al. 2021

ACS Catal.

Self Cite

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“…Unlike other Hsp90 family chaperones, which interact with proteins mainly involved in signal transduction and cell maintenance and growth, TRAP1 has been suggested to interact with other mitochondrial chaperones such as Hsp60 and mtHsp70 and with several other proteins involved in mitochondrial homeostasis and bioenergetics, including mitochondrial respiratory subunits [20][21][22][23]. The mechanism by which TRAP1 confers neuroprotection is complex.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Expression of TRAP1 Protects Mitochondrial Function in Motor Neurons under Conditions of Oxidative Stress

Clarke

Kalmár²,

Greensmith

2022

IJMS

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TNF-receptor associated protein (TRAP1) is a cytoprotective mitochondrial-specific member of the Hsp90 heat shock protein family of protein chaperones that has been shown to antagonise mitochondrial apoptosis and oxidative stress, regulate the mitochondrial permeability transition pore and control protein folding in mitochondria. Here we show that overexpression of TRAP1 protects motor neurons from mitochondrial dysfunction and death induced by exposure to oxidative stress conditions modelling amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease in which motor neurons degenerate, leading to muscle weakness and atrophy and death, typically within 3 years of diagnosis. In primary murine motor neurons, shRNA-mediated knockdown of TRAP1 expression results in mitochondrial dysfunction but does not further exacerbate damage induced by oxidative stress alone. Together, these results show that TRAP1 may be a potential therapeutic target for neurodegenerative diseases such as ALS, where mitochondrial dysfunction has been shown to be an early marker of pathogenesis.

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“…Controversially, TRAP1 has alternately been characterized as an oncogene and tumor suppressor, and it has been suggested that TRAP1 is essential for malignant transformation of cells but dispensable at later stages of tumor development [ 6 , 27 ]. Despite this controversy, much of the literature supports the idea that TRAP1 regulates metabolic transformation during tumorigenesis, TRAP1 is overexpressed in many cancers, and TRAP1 attenuation is detrimental to tumor cell survival [ 28 , 29 , 30 , 31 , 32 , 33 ]. It may be more appropriate to suggest that, similar to cytosolic Hsp90, many cancers may be ‘addicted’ to TRAP1 [ 34 , 35 , 36 ].…”

Section: Impact Of Trap1 On Cancer Metabolismmentioning

confidence: 99%

“…Conjugation to a chemical scaffold such as the mitochondrial-targeting moiety triphenylphosphonium (TPP) is necessary to provide mitochondrial penetrance [ 116 , 117 ]. Specificity for TRAP1 over Hsp90 may also be a necessary consideration, as well-established Hsp90 ATP-competitive inhibitors cannot differentiate between the ATP-binding pockets, potentially leading to off-target toxicity [ 33 ].…”

Section: Current State Of Trap1 Inhibitor Developmentmentioning

confidence: 99%

TRAP1 Chaperones the Metabolic Switch in Cancer

et al. 2022

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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.

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Targeting the mitochondrial chaperone TRAP1: strategies and therapeutic perspectives

Cited by 23 publications

References 67 publications

Atomistic Simulations of the Mechanisms of the Poorly Catalytic Mitochondrial Chaperone Trap1: Insights into the Effects of Structural Asymmetry on Reactivity

Atomistic Simulations of the Mechanisms of the Poorly Catalytic Mitochondrial Chaperone Trap1: Insights into the Effects of Structural Asymmetry on Reactivity

Enhanced Expression of TRAP1 Protects Mitochondrial Function in Motor Neurons under Conditions of Oxidative Stress

TRAP1 Chaperones the Metabolic Switch in Cancer

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