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The 26S Proteasomal ATPases: Structure, Function, Regulation, and Potential for Cancer Therapies

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Resistance to Proteasome Inhibitors in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT))

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Abstract

The 26S proteasome is the only protein degradation machine in the cell that selectively degrades proteins, and as such it regulates the vast majority of cellular processes (e.g., cell proliferation, differentiation, transcription, and signal transduction), and it is essential for cell survival. The multistep process of protein degradation by the 26S proteasome begins with the recognition of substrates by the 19S regulatory particle and ends with their degradation inside the 20S core particle. Inhibitors of the 20S proteolytic sites (e.g., by bortezomib and carfilzomib) have proven useful for the treatment of hematological cancers, especially multiple myeloma, where bortezomib is used as a first-line treatment. However, relapse typically occurs in these patients and drug resistance is observed. Alternative therapeutic targets within the 26S proteasome—especially in 19S regulatory complex—are highly attractive due to the proven requirement for ubiquitin-dependent protein degradation in multiple myeloma. Because the 19S regulatory particle must catalyze a complex multiple step processes to stimulate the degradation of proteins, there are many attractive sites that could be targeted for new cancer therapies. We summarize recent developments in our understanding of the structure, function, and regulation of the 19S ATPases complex and the potential for pharmacological manipulation of the 19S and its ATPases to develop new classes of compounds that inhibit proteasomal regulation rather than global protein degradation, which we expect will have therapeutic advantages.

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Abbreviations

AAA + ATPases:

ATPases associated with diverse cellular activities

CaMKII:

Ca2+/calmodulin-dependent kinase II

CC:

Coiled coil

CP:

Core particle

DUB:

Deubiquitinating enzyme

EM:

Electron microscopy

HbYX:

Hydrophobic (Hb), tyrosine (Y), and any residue (X)

OB:

Oligonucleotide/oligosaccharide binding

OGT:

O-GlcNAc transferase

PA28:

Proteasome activator 28 kDa

PAN:

Proteasome-activating nucleotidase

PI31:

Proteasome inhibitor 31 kDa

PKA:

Protein kinase A

PTMs:

Posttranslational modifications

RP:

Regulatory particle

RPN:

Regulatory particle non-ATPase

RPT:

Regulatory particle ATPase

UBA-UBL domain:

Ubiquitin-associated-ubiquitin-like domain

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Authors and Affiliations

  1. Department of Biochemistry, West Virginia University School of Medicine, 1 Medical Center Drive, Morgantown, WV, 26506, USA

    Young-Chan Kim & David M. Smith

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  1. Young-Chan Kim
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  2. David M. Smith
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Correspondence to David M. Smith .

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Editors and Affiliations

  1. Wayne State University, Detroit, Michigan, USA

    Q. Ping Dou

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Kim, YC., Smith, D.M. (2014). The 26S Proteasomal ATPases: Structure, Function, Regulation, and Potential for Cancer Therapies. In: Dou, Q. (eds) Resistance to Proteasome Inhibitors in Cancer. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-06752-0_14

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