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Biomolecules
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Allosteric Regulation in Ubiquitin Proteasome System
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Allosteric Regulation in Ubiquitin Proteasome System

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (20 June 2023) | Viewed by 17717

Special Issue Editors

Dr. Maria E. Gaczyńska

E-Mail Website
Guest Editor
Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA
Interests: proteasome; allosteric proteasome regulators; ubiquitin-proteasome pathway in cancer, aging and immune response; protein allostery; protein biophysics; scanning probe microscopy; atomic force microscopy; single-cell biophysics; circulating tumor cells
Dr. Pawel A. Osmulski

E-Mail Website
Guest Editor
Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA
Interests: protein biophysics; spectroscopic methods; medicinal chemistry of the proteasome regulators; role of proteasome in cancer, aging and immune response; single-cell biophysics; atomic force microscopy; circulating tumor cells

Special Issue Information

Dear Colleagues,

As knowledge of the ubiquitin-proteasome system (UPS) has been accumulating, this multiprotein intracellular machinery has become recognized as one of the major guardians of proteostasis. The proteasome, a key protease of the system, is now an acknowledged target for drugs. On a distinct level of molecular organization and with a longer supporting record, protein allostery has advanced from being considered a peculiar behavior of multisubunit proteins to established as a universal phenomenon regulating protein function. The paths of allostery and UPS have not crossed for a long time, as proteasome has been considered a non-allosteric protein, seemingly locked in elegant crystal structure models. However, further structural studies have started to reveal the dynamics and allosteric regulation involved in proteasome assembly. In parallel, multiple examples of allosteric interactions have been uncovered in the polyubiquitination machinery, most notably for ubiquitin ligases and their protein partners and substrates. Since impairment or vulnerability of intracellular proteostasis is a hallmark of many diseases, harnessing allosteric interactions for regulation of the proteasome and other components of UPS would offer rich opportunities of translational significance. So far, the only proteasome-targeting drugs used in clinics are competitive inhibitors as anticancer agents. Since allosteric drugs may offer exceptionally diverse actions with low toxicity and superb specificity, it is of no surprise that multiple allosteric regulators of the proteasome and proteins involved in polyubiquitination are in preclinical development, with an eye on cancer and neurodegenerative diseases.

This Special Issue aims to present the rich and diverse aspects of allosteric regulation, both intrinsic and drug-related, in the ubiquitin-proteasome system.

Dr. Maria E. Gaczyńska
Dr. Pawel A. Osmulski
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • proteasome
  • ubiquitin proteasome system
  • allostery
  • allosteric regulators
  • proteostasis

Published Papers (7 papers)

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Research

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16 pages, 7539 KiB  
Article
A Role for the Proteasome Alpha2 Subunit N-Tail in Substrate Processing
by Indrajit Sahu, Monika Bajorek, Xiaolin Tan, Madabhushi Srividya, Daria Krutauz, Noa Reis, Pawel A. Osmulski, Maria E. Gaczynska and Michael H. Glickman
Biomolecules 2023, 13(3), 480; https://0-doi-org.brum.beds.ac.uk/10.3390/biom13030480 - 05 Mar 2023
Viewed by 1546
Abstract
The proteolytic active sites of the 26S proteasome are sequestered within the catalytic chamber of its 20S core particle (CP). Access to this chamber is through a narrow channel defined by the seven outer α subunits. In the resting state, the N-termini of [...] Read more.
The proteolytic active sites of the 26S proteasome are sequestered within the catalytic chamber of its 20S core particle (CP). Access to this chamber is through a narrow channel defined by the seven outer α subunits. In the resting state, the N-termini of neighboring α subunits form a gate blocking access to the channel. The attachment of the activators or regulatory particles rearranges the blocking α subunit N-termini facilitating the entry of substrates. By truncating or mutating each of the participating α N-termini, we report that whereas only a few N-termini are important for maintaining the closed gate, all seven N-termini participate in the open gate. Specifically, the open state is stabilized by a hydrogen bond between an invariant tyrosine (Y) in each subunit with a conserved aspartate (D) in its counterclockwise neighbor. The lone exception is the α1–α2 pair leaving a gap in the ring circumference. The third residue (X) of this YD(X) motif aligns with the open channel. Phenylalanine at this position in the α2 subunit comes in direct contact with the translocating substrate. Consequently, deletion of the α2 N-terminal tail attenuates proteolysis despite the appearance of an open gate state. In summary, the interlacing N-terminal YD(X) motifs regulate both the gating and translocation of the substrate. Full article
(This article belongs to the Special Issue Allosteric Regulation in Ubiquitin Proteasome System)
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13 pages, 2706 KiB  
Article
Peptidomimetics Based on C-Terminus of Blm10 Stimulate Human 20S Proteasome Activity and Promote Degradation of Proteins
by Katarzyna Cekała, Karolina Trepczyk, Daria Sowik, Przemysław Karpowicz, Artur Giełdoń, Julia Witkowska, Małgorzata Giżyńska, Elżbieta Jankowska and Ewa Wieczerzak
Biomolecules 2022, 12(6), 777; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12060777 - 02 Jun 2022
Cited by 1 | Viewed by 1692
Abstract
Degradation of misfolded, redundant and oxidatively damaged proteins constitutes one of the cellular processes which are influenced by the 20S proteasome. However, its activity is generally thought to decrease with age which leads to the gradual accumulation of abnormal proteins in cells and [...] Read more.
Degradation of misfolded, redundant and oxidatively damaged proteins constitutes one of the cellular processes which are influenced by the 20S proteasome. However, its activity is generally thought to decrease with age which leads to the gradual accumulation of abnormal proteins in cells and their subsequent aggregation. Therefore, increasing proteasomal degradation constitutes a promising strategy to delay the onset of various age-related diseases, including neurodegenerative disorders. In this study we designed and obtained a series of peptidomimetic stimulators of 20S comprising in their sequences the C-terminal fragment of Blm10 activator. Some of the compounds were capable of enhancing the degradation of natively unfolded and oxidatively damaged proteins, such as α-synuclein and enolase, whose applicability as proteasome substrates was evaluated by microscale thermophoresis (MST). Furthermore, they increased the ChT-L activity of the proteasome in HEK293T cell extracts. Our studies indicate that the 20S proteasome-mediated protein substrates hydrolysis may be selectively increased by peptide-based stimulators acting in an allosteric manner. These compounds, after further optimization, may have the potential to counteract proteasome impairment in patients suffering from age-related diseases. Full article
(This article belongs to the Special Issue Allosteric Regulation in Ubiquitin Proteasome System)
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27 pages, 6499 KiB  
Article
Modulation of the 20S Proteasome Activity by Porphyrin Derivatives Is Steered through Their Charge Distribution
by Marco Persico, Anna Maria Santoro, Alessandro D’Urso, Danilo Milardi, Roberto Purrello, Alessandra Cunsolo, Marina Gobbo, Roberto Fattorusso, Donatella Diana, Manuela Stefanelli, Grazia R. Tundo, Diego Sbardella, Massimo Coletta and Caterina Fattorusso
Biomolecules 2022, 12(6), 741; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12060741 - 24 May 2022
Viewed by 2001
Abstract
Cationic porphyrins exhibit an amazing variety of binding modes and inhibition mechanisms of 20S proteasome. Depending on the spatial distribution of their electrostatic charges, they can occupy different sites on α rings of 20S proteasome by exploiting the structural code responsible for the [...] Read more.
Cationic porphyrins exhibit an amazing variety of binding modes and inhibition mechanisms of 20S proteasome. Depending on the spatial distribution of their electrostatic charges, they can occupy different sites on α rings of 20S proteasome by exploiting the structural code responsible for the interaction with regulatory proteins. Indeed, they can act as competitive or allosteric inhibitors by binding at the substrate gate or at the grooves between the α subunits, respectively. Moreover, the substitution of a charged moiety in the peripheral arm with a hydrophobic moiety revealed a “new” 20S functional state with higher substrate affinity and catalytic efficiency. In the present study, we expand our structure–activity relationship (SAR) analysis in order to further explore the potential of this versatile class of 20S modulators. Therefore, we have extended the study to additional macrocyclic compounds, displaying different structural features, comparing their interaction behavior on the 20S proteasome with previously investigated compounds. In particular, in order to evaluate how the introduction of a peptidic chain can affect the affinity and the interacting mechanism of porphyrins, we investigate the MTPyApi, a porphyrin derivatized with an Arg–Pro-rich antimicrobial peptide. Moreover, to unveil the role played by the porphyrin core, this was replaced with a corrole scaffold, a “contracted” version of the tetrapyrrolic ring due to the lack of a methine bridge. The analysis has been undertaken by means of integrated kinetic, Nuclear Magnetic Resonance, and computational studies. Finally, in order to assess a potential pharmacological significance of this type of investigation, a preliminary attempt has been performed to evaluate the biological effect of these molecules on MCF7 breast cancer cells in dark conditions, envisaging that porphyrins may indeed represent a powerful tool for the modulation of cellular proteostasis. Full article
(This article belongs to the Special Issue Allosteric Regulation in Ubiquitin Proteasome System)
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Review

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18 pages, 4098 KiB  
Review
Structure, Function, and Allosteric Regulation of the 20S Proteasome by the 11S/PA28 Family of Proteasome Activators
by Taylor Thomas, David Salcedo-Tacuma and David M. Smith
Biomolecules 2023, 13(9), 1326; https://0-doi-org.brum.beds.ac.uk/10.3390/biom13091326 - 29 Aug 2023
Viewed by 1229
Abstract
The proteasome, a complex multi-catalytic protease machinery, orchestrates the protein degradation essential for maintaining cellular homeostasis, and its dysregulation also underlies many different types of diseases. Its function is regulated by many different mechanisms that encompass various factors such as proteasome activators (PAs), [...] Read more.
The proteasome, a complex multi-catalytic protease machinery, orchestrates the protein degradation essential for maintaining cellular homeostasis, and its dysregulation also underlies many different types of diseases. Its function is regulated by many different mechanisms that encompass various factors such as proteasome activators (PAs), adaptor proteins, and post-translational modifications. This review highlights the unique characteristics of proteasomal regulation through the lens of a distinct family of regulators, the 11S, REGs, or PA26/PA28. This ATP-independent family, spanning from amoebas to mammals, exhibits a common architectural structure; yet, their cellular biology and criteria for protein degradation remain mostly elusive. We delve into their evolution and cellular biology, and contrast their structure and function comprehensively, emphasizing the unanswered questions regarding their regulatory mechanisms and broader roles in proteostasis. A deeper understanding of these processes will illuminate the roles of this regulatory family in biology and disease, thus contributing to the advancement of therapeutic strategies. Full article
(This article belongs to the Special Issue Allosteric Regulation in Ubiquitin Proteasome System)
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21 pages, 4395 KiB  
Review
Wiggle and Shake: Managing and Exploiting Conformational Dynamics during Proteasome Biogenesis
by Daniel Betancourt, Tomiwa Lawal and Robert J. Tomko, Jr.
Biomolecules 2023, 13(8), 1223; https://0-doi-org.brum.beds.ac.uk/10.3390/biom13081223 - 06 Aug 2023
Viewed by 1338
Abstract
The 26S proteasome is the largest and most complicated protease known, and changes to proteasome assembly or function contribute to numerous human diseases. Assembly of the 26S proteasome from its ~66 individual polypeptide subunits is a highly orchestrated process requiring the concerted actions [...] Read more.
The 26S proteasome is the largest and most complicated protease known, and changes to proteasome assembly or function contribute to numerous human diseases. Assembly of the 26S proteasome from its ~66 individual polypeptide subunits is a highly orchestrated process requiring the concerted actions of both intrinsic elements of proteasome subunits, as well as assistance by extrinsic, dedicated proteasome assembly chaperones. With the advent of near-atomic resolution cryo-electron microscopy, it has become evident that the proteasome is a highly dynamic machine, undergoing numerous conformational changes in response to ligand binding and during the proteolytic cycle. In contrast, an appreciation of the role of conformational dynamics during the biogenesis of the proteasome has only recently begun to emerge. Herein, we review our current knowledge of proteasome assembly, with a particular focus on how conformational dynamics guide particular proteasome biogenesis events. Furthermore, we highlight key emerging questions in this rapidly expanding area. Full article
(This article belongs to the Special Issue Allosteric Regulation in Ubiquitin Proteasome System)
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27 pages, 2587 KiB  
Review
Advances in Proteasome Enhancement by Small Molecules
by Dare E. George and Jetze J. Tepe
Biomolecules 2021, 11(12), 1789; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11121789 - 30 Nov 2021
Cited by 12 | Viewed by 6250
Abstract
The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate [...] Read more.
The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate degradation with small molecules may therefore be a valuable strategy for the treatment of various neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. In this review, we discuss the structure of proteasome and how proteasome’s proteolytic activity is associated with aging and various neurodegenerative diseases. We also summarize various classes of compounds that are capable of enhancing, directly or indirectly, proteasome-mediated protein degradation. Full article
(This article belongs to the Special Issue Allosteric Regulation in Ubiquitin Proteasome System)
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Other

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6 pages, 689 KiB  
Perspective
PCNA Ubiquitylation: Instructive or Permissive to DNA Damage Tolerance Pathways?
by Jun Che, Xin Hong and Hai Rao
Biomolecules 2021, 11(10), 1543; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11101543 - 19 Oct 2021
Cited by 4 | Viewed by 2595
Abstract
DNA lesions escaping from repair often block the DNA replicative polymerases required for DNA replication and are handled during the S/G2 phases by the DNA damage tolerance (DDT) mechanisms, which include the error-prone translesion synthesis (TLS) and the error-free template switching (TS) pathways. [...] Read more.
DNA lesions escaping from repair often block the DNA replicative polymerases required for DNA replication and are handled during the S/G2 phases by the DNA damage tolerance (DDT) mechanisms, which include the error-prone translesion synthesis (TLS) and the error-free template switching (TS) pathways. Where the mono-ubiquitylation of PCNA K164 is critical for TLS, the poly-ubiquitylation of the same residue is obligatory for TS. However, it is not known how cells divide the labor between TLS and TS. Due to the fact that the type of DNA lesion significantly influences the TLS and TS choice, we propose that, instead of altering the ratio between the mono- and poly-Ub forms of PCNA, the competition between TLS and TS would automatically determine the selection between the two pathways. Future studies, especially the single integrated lesion “i-Damage” system, would elucidate detailed mechanisms governing the choices of specific DDT pathways. Full article
(This article belongs to the Special Issue Allosteric Regulation in Ubiquitin Proteasome System)
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