AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors

Zhang, Gang; Li, Shan; Cheng, Kai-Wen; Chou, Tsui‐Fen

doi:10.1016/j.ejmech.2021.113446

Cited by 34 publications

(29 citation statements)

References 156 publications

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“…RuvBL1 (synonyms: Pontin52, Rvb1, TAP54a, and TIP49) is a highly conserved ATPase of the AAA+ (ATPases Associated with various cellular Activities) superfamily, and possesses intrinsic ATPase activities and DNA helicase activities (14)(15)(16). It is involved in various cellular processes, such as transcription, DNA damage, cellular transformation and cancer metastasis (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

RuvBL1 Maintains Resistance to TRAIL-Induced Apoptosis by Suppressing c-Jun/AP-1 Activity in Non-Small Cell Lung Cancer

Zhou²,

Zhang³

et al. 2021

Front. Oncol.

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Lung cancer is the common malignant tumor with the highest death rate in the world. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a potential anticancer agent induces selective apoptotic death of human cancer cells. Unfortunately, approximately half of lung cancer cell lines are intrinsically resistant to TRAIL-induced cell death. In this study, we identified RuvBL1 as a repressor of c-Jun/AP-1 activity, contributing to TRAIL resistance in lung cancer cells. Knocking down RuvBL1 effectively sensitized resistant cells to TRAIL, and overexpression of RuvBL1 inhibited TRAIL-induced apoptosis. Moreover, there was a negative correlation expression between RuvBL1 and c-Jun in lung adenocarcinoma by Oncomine analyses. High expression of RuvBL1 inversely with low c-Jun in lung cancer was associated with a poor overall prognosis. Taken together, our studies broaden the molecular mechanisms of TRAIL resistance and suggest the application of silencing RuvBL1 synergized with TRAIL to be a novel therapeutic strategy in lung cancer treatment.

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Section: Introductionmentioning

confidence: 99%

RuvBL1 Maintains Resistance to TRAIL-Induced Apoptosis by Suppressing c-Jun/AP-1 Activity in Non-Small Cell Lung Cancer

Zhou²,

Zhang³

et al. 2021

Front. Oncol.

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“…These amino acids play important roles in the binding and hydrolysis of ATP (Fig. 4e) (Yedidi et al, 2017; Zhang et al, 2021; Zhang and Mao, 2020). Indeed, when these mutations were introduced, not only the disaggregase activity was abolished, but the ATPase activity was significantly impaired (Warren et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Insights into the Action Mode of A Mitochondrial AAA+ Disaggregase CLPB

Liu

Dai

et al. 2022

Preprint

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The human AAA+ ATPase CLPB (aka, HSP78 and Skd3) is a protein disaggregase and functions to promote the solubilization of proteins in the mitochondrial intermembrane space. Unlike other AAA+ protein unfoldases or disaggregases, CLPB contains an ankyrin repeat containing domain (ANK) at its N-terminus. Mutations of CLPB are closely associated with a few human diseases, such as 3-methylglutaconic aciduria (3-MGA) and severe congenital neutropenia (SCN). The mechanism of CLPB functions as a disaggregase and the role of its unique ANK domain are currently unclear. Herein, we report a comprehensive structural characterization of human CLPB in both the apo- and substrate-bound states. Our data show that CLPB assembles into homo-tetradecamers in apo-state and dodecamers in the presence of a substrate, mediated by ANK domains via a "head-to-head" organization. Conserved pore-loops (PLs) on the ATPase domains form a spiral staircase to grasp and translocate the substrate in a step-size of two amino acid residues. We also show that the ANK domain is functionally essential, and more important, responsible for direct binding to various mitocondiral proteins in the inner membrane or intermembrane space. These results suggest that CLPB functions as a general disaggregase in mitochondria and highlight its potential as a target for the treatment of various mitochondria-related diseases.

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“…ATAD2 can be divided into four regions, N-terminal acidic domain, AAA ATPase domain (AAA-ATAD2), bromodomain, and C-terminal domain ( Figure 1 ). AAA-ATAD2 contains Walker A, Walker B, sensor 1, sensor 2, and an arginine finger and functions as a hexameric compound [ 7 ]. The bromodomain has four α-helix bundles and ZA and BC loops between the two helices, which contain several amino acids necessary to interacting with acetylated lysines to form a hydrophobic pocket [ 71 ].…”

Section: Atad2 Is a Member Of Bromodomain-containing Proteinsmentioning

confidence: 99%

“…There are two isoforms of human ATAD2 , known as ATAD2A and ATAD2B [ 4 ], and most published functional studies have been done on ATAD2/ATAD2A; hence, ATAD2 is also the focal point of our review. ATAD2 is mainly expressed in male genital cells [ 5 ] and has two conserved protein domains, AAA ATPase and bromodomain (BRD), which are the main structures for its biological functions [ 6 , 7 ]. Studies have shown that ATAD2 acts as an epigenetic decoder and transcription factor or coactivator involved in many cellular processes, such as DNA replication [ 8 ], transcriptional regulation [ 9 ], protein modification [ 10 ], and cell proliferation [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Tumor-Promoting ATAD2 and Its Preclinical Challenges

et al. 2022

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ATAD2 has received extensive attention in recent years as one prospective oncogene with tumor-promoting features in many malignancies. ATAD2 is a highly conserved bromodomain family protein that exerts its biological functions by mainly AAA ATPase and bromodomain. ATAD2 acts as an epigenetic decoder and transcription factor or co-activator, which is engaged in cellular activities, such as transcriptional regulation, DNA replication, and protein modification. ATAD2 has been reported to be highly expressed in a variety of human malignancies, including gastrointestinal malignancies, reproductive malignancies, urological malignancies, lung cancer, and other types of malignancies. ATAD2 is involved in the activation of multiple oncogenic signaling pathways and is closely associated with tumorigenesis, progression, chemoresistance, and poor prognosis, but the oncogenic mechanisms vary in different cancer types. Moreover, the direct targeting of ATAD2’s bromodomain may be a very challenging task. In this review, we summarized the role of ATAD2 in various types of malignancies and pointed out the pharmacological direction.

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AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors

Cited by 34 publications

References 156 publications

RuvBL1 Maintains Resistance to TRAIL-Induced Apoptosis by Suppressing c-Jun/AP-1 Activity in Non-Small Cell Lung Cancer

RuvBL1 Maintains Resistance to TRAIL-Induced Apoptosis by Suppressing c-Jun/AP-1 Activity in Non-Small Cell Lung Cancer

Structural and Functional Insights into the Action Mode of A Mitochondrial AAA+ Disaggregase CLPB

Tumor-Promoting ATAD2 and Its Preclinical Challenges

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