Specificity for latent C termini links the E3 ubiquitin ligase CHIP to caspases

Ravalin, Matthew; Theofilas, Panagiotis; Basu, Koli; Opoku-Nsiah, Kwadwo; Assimon, Victoria A.; Medina-Cleghorn, Daniel; Chen, Yifan; Bohn, Markus-Frederik; Arkin, Michelle R.; Grinberg, Lea T.; Craik, Charles S.; Gestwicki, Jason E.

doi:10.1038/s41589-019-0322-6

Cited by 66 publications

(70 citation statements)

References 54 publications

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“…Since a full-length crystal structure of human HSP70 protein has not yet been obtained, we have used the structures of its two major domains such as NBD and SBD in their bound and free forms. The structures of HSP70 domains and all proteins/receptors used for docking were obtained from the Protein Data Bank (PDB) ( Supplementary Table S1) [17][18][19][20][21][22][23][24][25][26][27][28][29]. The molecules of interest were extracted from the models according to the identifier of the peptide chain (Supplementary Table S1).…”

Section: Hsp70 Receptorsmentioning

confidence: 99%

HSP70 Multi-Functionality in Cancer

Albakova

Армеев

Kanevskiy

et al. 2020

Cells

189

141

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The 70-kDa heat shock proteins (HSP70s) are abundantly present in cancer, providing malignant cells selective advantage by suppressing multiple apoptotic pathways, regulating necrosis, bypassing cellular senescence program, interfering with tumor immunity, promoting angiogenesis and supporting metastasis. This direct involvement of HSP70 in most of the cancer hallmarks explains the phenomenon of cancer “addiction” to HSP70, tightly linking tumor survival and growth to the HSP70 expression. HSP70 operates in different states through its catalytic cycle, suggesting that it can multi-function in malignant cells in any of these states. Clinically, tumor cells intensively release HSP70 in extracellular microenvironment, resulting in diverse outcomes for patient survival. Given its clinical significance, small molecule inhibitors were developed to target different sites of the HSP70 machinery. Furthermore, several HSP70-based immunotherapy approaches were assessed in clinical trials. This review will explore different roles of HSP70 on cancer progression and emphasize the importance of understanding the flexibility of HSP70 nature for future development of anti-cancer therapies.

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Section: Hsp70 Receptorsmentioning

confidence: 99%

HSP70 Multi-Functionality in Cancer

Albakova

Армеев

Kanevskiy

et al. 2020

Cells

189

141

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“…The action of N-and C-degron pathways on the resulting 'neo-termini' can dramatically alter the fate of the cleavage products. Ravalin and colleagues recently uncovered a C-degron pathway in which the E3 ligase CHIP targets substrates terminating with aspartic acid [48]. The C-terminal tails of the chaperones Hsp70 and Hsp90 were thought to be the primary interacting partners for the TPR repeats of CHIP [58,59], but, by assaying CHIP binding to a library of short peptides that all terminated in aspartate, the authors found that CHIP could potentially bind hundreds of C-termini exposed following caspase cleavage [48].…”

Section: Regulate Fate Following Protease Cleavagementioning

confidence: 99%

“…Ravalin and colleagues recently uncovered a C-degron pathway in which the E3 ligase CHIP targets substrates terminating with aspartic acid [48]. The C-terminal tails of the chaperones Hsp70 and Hsp90 were thought to be the primary interacting partners for the TPR repeats of CHIP [58,59], but, by assaying CHIP binding to a library of short peptides that all terminated in aspartate, the authors found that CHIP could potentially bind hundreds of C-termini exposed following caspase cleavage [48]. On the other hand, we demonstrated that hundreds of known caspase cleavage events within the cell will generate N-terminal glycine degrons targeted by Cul2 ZYG11B and Cul2 ZER1 [27].…”

Section: Regulate Fate Following Protease Cleavagementioning

confidence: 99%

“…We speculate that additional end-directed E3 ligases may enforce the faithful incorporation of these modifications into target proteins. [62] Arg/N-degron C-terminal fragments generated by calpain cleavage UBRs [78] Gly/N-degron C-terminal fragments generated by caspase cleavage Cul2 ZYG11B Cul2 ZER1 [27] Asp/C-degron N-terminal fragments generated by caspase cleavage CHIP [48] Gly/C-degron Autocleaved Usp1 Cul2 KLHDC2 [16] Mediate cross-talk with autophagy [66] Gly/N-degron N-myristoylated proteins Cul2 ZYG11B Cul2 ZER1 [27] All of these potential functions for terminal degron pathwaysand some additional onesare summarised in Table 1.…”

Section: Enforce Faithful Incorporation Of Post-translational Modificmentioning

confidence: 99%

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Tying up loose ends: the N-degron and C-degron pathways of protein degradation

Timms

Koren

2020

Biochemical Society Transactions

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Selective protein degradation by the ubiquitin-proteasome system (UPS) is thought to be governed primarily by the recognition of specific motifs — degrons — present in substrate proteins. The ends of proteins — the N- and C-termini – have unique properties, and an important subset of protein–protein interactions involve the recognition of free termini. The first degrons to be discovered were located at the extreme N-terminus of proteins, a finding which initiated the study of the N-degron (formerly N-end rule) pathways, but only in the last few years has it emerged that a diverse set of C-degron pathways target analogous degron motifs located at the extreme C-terminus of proteins. In this minireview we summarise the N-degron and C-degron pathways currently known to operate in human cells, focussing primarily on those that have been discovered in recent years. In each case we describe the cellular machinery responsible for terminal degron recognition, and then consider some of the functional roles of terminal degron pathways. Altogether, a broad spectrum of E3 ubiquitin ligases mediate the recognition of a diverse array of terminal degron motifs; these degradative pathways have the potential to influence a wide variety of cellular functions.

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“…Notably, CHIP presents high affinity for truncated Asp-421 TAU generated by caspase cleavage, with preferential poly-ubiquitination of this potentially pathogenic form when compared to full-length TAU. This latter demonstrated by decreased CHIP levels and increased Asp-421 TAU during AD progression [155]. TAU lesions in postmortem tissue are immune positive for CHIP, but CHIP may also accelerate TAU multimerization [156].…”

Section: The Interaction Of Tau With Proteins Linked To Cancermentioning

confidence: 99%

Tau: At the Interface Between Neurodegeneration and Cancer?

Papin¹,

Paganetti²

2020

Preprint

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For its microtubule-binding properties, the expression level of the neurodegeneration-associated protein Tau is pondered as a potential modifier of cancer resistance to chemotherapy since decades. Indeed, Tau binds microtubules at the same site as taxanes, a class of chemotherapeutic drugs designed to stabilize the microtubule network in order to stall cell division and to induce tumor cell death. Whilst independent studies report the association between low Tau expression and superior taxane response, the data were refused by a meta-analysis, suggesting interference of other parameters. Unpredictably, Tau expression level was identified as a prognostic cancer marker, whereby its positive or negative predictive value for survival depended on the cancer type. With recent experimental evidence linking Tau to P53 signaling, DNA stability and protection and to the implication of Tau in cancer is strengthened. The identification of a role of Tau at the interface between two major aging-related disorder families, neurodegeneration and cancer, offers clues for the epidemiological observation inversely correlating these disorders. Elucidating how Tau is mechanistically implicated in cellular pathways common to these devastating illnesses may extend the Tau-targeting therapeutic opportunities to cancer.

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Specificity for latent C termini links the E3 ubiquitin ligase CHIP to caspases

Cited by 66 publications

References 54 publications

HSP70 Multi-Functionality in Cancer

HSP70 Multi-Functionality in Cancer

Tying up loose ends: the N-degron and C-degron pathways of protein degradation

Tau: At the Interface Between Neurodegeneration and Cancer?

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