scholarly journals Mechanisms, regulation and consequences of protein SUMOylation

2010 ◽  
Vol 428 (2) ◽  
pp. 133-145 ◽  
Author(s):  
Kevin A. Wilkinson ◽  
Jeremy M. Henley
Keyword(s):  
Protein Function ◽  
Covalent Attachment ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Wide Range ◽  
Lysine Residues ◽  
Ubiquitination Pathway ◽  
Regulate Protein ◽  
Substrate Proteins ◽  
Protein Sumoylation

The post-translational modification SUMOylation is a major regulator of protein function that plays an important role in a wide range of cellular processes. SUMOylation involves the covalent attachment of a member of the SUMO (small ubiquitin-like modifier) family of proteins to lysine residues in specific target proteins via an enzymatic cascade analogous to, but distinct from, the ubiquitination pathway. There are four SUMO paralogues and an increasing number of proteins are being identified as SUMO substrates. However, in many cases little is known about how SUMOylation of these targets is regulated. Compared with the ubiquitination pathway, relatively few components of the conjugation machinery have been described and the processes that specify individual SUMO paralogue conjugation to defined substrate proteins are an active area of research. In the present review, we briefly describe the SUMOylation pathway and present an overview of the recent findings that are beginning to identify some of the mechanisms that regulate protein SUMOylation.

scholarly journals Post-translational regulation of ubiquitin signaling

2019 ◽  
Vol 218 (6) ◽  
pp. 1776-1786 ◽  
Author(s):  
Lei Song ◽  
Zhao-Qing Luo
Keyword(s):  
Translational Regulation ◽  
Covalent Attachment ◽  
Immune Disorders ◽  
Post Translational Modification ◽  
Polyubiquitin Chains ◽  
Cellular Processes ◽  
Lysine Residues ◽  
Substrate Proteins ◽  
Ubiquitination Machinery ◽  
Integrate Development

Ubiquitination regulates many essential cellular processes in eukaryotes. This post-translational modification (PTM) is typically achieved by E1, E2, and E3 enzymes that sequentially catalyze activation, conjugation, and ligation reactions, respectively, leading to covalent attachment of ubiquitin, usually to lysine residues of substrate proteins. Ubiquitin can also be successively linked to one of the seven lysine residues on ubiquitin to form distinctive forms of polyubiquitin chains, which, depending upon the lysine used and the length of the chains, dictate the fate of substrate proteins. Recent discoveries revealed that this ubiquitin code is further expanded by PTMs such as phosphorylation, acetylation, deamidation, and ADP-ribosylation, on ubiquitin, components of the ubiquitination machinery, or both. These PTMs provide additional regulatory nodes to integrate development or insulting signals with cellular homeostasis. Understanding the precise roles of these PTMs in the regulation of ubiquitin signaling will provide new insights into the mechanisms and treatment of various human diseases linked to ubiquitination, including neurodegenerative diseases, cancer, infection, and immune disorders.

scholarly journals Bioinformatics analysis reveals biophysical and evolutionary insights into the 3-nitrotyrosine post-translational modification in the human proteome

Open Biology ◽  
2013 ◽  
Vol 3 (2) ◽  
pp. 120148 ◽  
Author(s):  
John Y. Ng ◽  
Lies Boelen ◽  
Jason W. H. Wong
Keyword(s):  
Protein Function ◽  
Bioinformatics Analysis ◽  
Proteome Analysis ◽  
Human Proteome ◽  
Prediction Algorithm ◽  
Post Translational Modification ◽  
Tyrosine Residues ◽  
Cellular Processes ◽  
Wide Range ◽  
Human Proteins

Protein 3-nitrotyrosine is a post-translational modification that commonly arises from the nitration of tyrosine residues. This modification has been detected under a wide range of pathological conditions and has been shown to alter protein function. Whether 3-nitrotyrosine is important in normal cellular processes or is likely to affect specific biological pathways remains unclear. Using GPS-YNO2, a recently described 3-nitrotyrosine prediction algorithm, a set of predictions for nitrated residues in the human proteome was generated. In total, 9.27 per cent of the proteome was predicted to be nitratable (27 922/301 091). By matching the predictions against a set of curated and experimentally validated 3-nitrotyrosine sites in human proteins, it was found that GPS-YNO2 is able to predict 73.1 per cent (404/553) of these sites. Furthermore, of these sites, 42 have been shown to be nitrated endogenously, with 85.7 per cent (36/42) of these predicted to be nitrated. This demonstrates the feasibility of using the predicted dataset for a whole proteome analysis. A comprehensive bioinformatics analysis was subsequently performed on predicted and all experimentally validated nitrated tyrosine. This found mild but specific biophysical constraints that affect the susceptibility of tyrosine to nitration, and these may play a role in increasing the likelihood of 3-nitrotyrosine to affect processes, including phosphorylation and DNA binding. Furthermore, examining the evolutionary conservation of predicted 3-nitrotyrosine showed that, relative to non-nitrated tyrosine residues, 3-nitrotyrosine residues are generally less conserved. This suggests that, at least in the majority of cases, 3-nitrotyrosine is likely to have a deleterious effect on protein function and less likely to be important in normal cellular function.

scholarly journals Structural, Evolutionary, and Functional Analysis of the Protein O-Mannosyltransferase Family in Pathogenic Fungi

2021 ◽  
Vol 7 (5) ◽  
pp. 328
Author(s):  
María Dolores Pejenaute-Ochoa ◽  
Carlos Santana-Molina ◽  
Damien P. Devos ◽  
José Ignacio Ibeas ◽  
Alfonso Fernández-Álvarez
Keyword(s):  
Functional Analysis ◽  
Secretory Pathway ◽  
Pathogenic Fungi ◽  
Fungal Pathogenesis ◽  
Post Translational Modification ◽  
Key Factors ◽  
Wide Range ◽  
Single Deletion ◽  
Asymmetrical Impact ◽  
Substrate Proteins

Protein O-mannosyltransferases (Pmts) comprise a group of proteins that add mannoses to substrate proteins at the endoplasmic reticulum. This post-translational modification is important for the faithful transfer of nascent glycoproteins throughout the secretory pathway. Most fungi genomes encode three O-mannosyltransferases, usually named Pmt1, Pmt2, and Pmt4. In pathogenic fungi, Pmts, especially Pmt4, are key factors for virulence. Although the importance of Pmts for fungal pathogenesis is well established in a wide range of pathogens, questions remain regarding certain features of Pmts. For example, why does the single deletion of each pmt gene have an asymmetrical impact on host colonization? Here, we analyse the origin of Pmts in fungi and review the most important phenotypes associated with Pmt mutants in pathogenic fungi. Hence, we highlight the enormous relevance of these glycotransferases for fungal pathogenic development.

scholarly journals The AAA+ ATPase p97, a cellular multitool

2017 ◽  
Vol 474 (17) ◽  
pp. 2953-2976 ◽  
Author(s):  
Lasse Stach ◽  
Paul S. Freemont
Keyword(s):  
Atp Hydrolysis ◽  
Current Status ◽  
Cellular Functions ◽  
Aaa Atpase ◽  
Cellular Processes ◽  
Proteotoxic Stress ◽  
Binding Domains ◽  
Wide Range ◽  
Aaa Atpases ◽  
Substrate Proteins

The AAA+ (ATPases associated with diverse cellular activities) ATPase p97 is essential to a wide range of cellular functions, including endoplasmic reticulum-associated degradation, membrane fusion, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and chromatin-associated processes, which are regulated by ubiquitination. p97 acts downstream from ubiquitin signaling events and utilizes the energy from ATP hydrolysis to extract its substrate proteins from cellular structures or multiprotein complexes. A multitude of p97 cofactors have evolved which are essential to p97 function. Ubiquitin-interacting domains and p97-binding domains combine to form bi-functional cofactors, whose complexes with p97 enable the enzyme to interact with a wide range of ubiquitinated substrates. A set of mutations in p97 have been shown to cause the multisystem proteinopathy inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia. In addition, p97 inhibition has been identified as a promising approach to provoke proteotoxic stress in tumors. In this review, we will describe the cellular processes governed by p97, how the cofactors interact with both p97 and its ubiquitinated substrates, p97 enzymology and the current status in developing p97 inhibitors for cancer therapy.

scholarly journals Development of a yeast model to study the contribution of vacuolar polyphosphate metabolism to lysine polyphosphorylation

2019 ◽  
Vol 295 (6) ◽  
pp. 1439-1451 ◽  
Author(s):  
Cristina Azevedo ◽  
Yann Desfougères ◽  
Yannasittha Jiramongkol ◽  
Hamish Partington ◽  
Sasanan Trakansuebkul ◽  
...  
Keyword(s):  
Cell Lysis ◽  
Covalent Attachment ◽  
Amino Acid Residues ◽  
Post Translational Modification ◽  
Target Domain ◽  
Inorganic Polyphosphate ◽  
Topoisomerase 1 ◽  
Lysine Residues ◽  
Polyphosphate Metabolism ◽  
Nuclear Targets

A recently-discovered protein post-translational modification, lysine polyphosphorylation (K-PPn), consists of the covalent attachment of inorganic polyphosphate (polyP) to lysine residues. The nonenzymatic nature of K-PPn means that the degree of this modification depends on both polyP abundance and the amino acids surrounding the modified lysine. K-PPn was originally discovered in budding yeast (Saccharomyces cerevisiae), in which polyP anabolism and catabolism are well-characterized. However, yeast vacuoles accumulate large amounts of polyP, and upon cell lysis, the release of the vacuolar polyP could nonphysiologically cause K-PPn of nuclear and cytosolic targets. Moreover, yeast vacuoles possess two very active endopolyphosphatases, Ppn1 and Ppn2, that could have opposing effects on the extent of K-PPn. Here, we characterized the contribution of vacuolar polyP metabolism to K-PPn of two yeast proteins, Top1 (DNA topoisomerase 1) and Nsr1 (nuclear signal recognition 1). We discovered that whereas Top1-targeting K-PPn is only marginally affected by vacuolar polyP metabolism, Nsr1-targeting K-PPn is highly sensitive to the release of polyP and of endopolyphosphatases from the vacuole. Therefore, to better study K-PPn of cytosolic and nuclear targets, we constructed a yeast strain devoid of vacuolar polyP by targeting the exopolyphosphatase Ppx1 to the vacuole and concomitantly depleting the two endopolyphosphatases (ppn1Δppn2Δ, vt-Ppx1). This strain enabled us to study K-PPn of cytosolic and nuclear targets without the interfering effects of cell lysis on vacuole polyP and of endopolyphosphatases. Furthermore, we also define the fundamental nature of the acidic amino acid residues to the K-PPn target domain.

Structural basis for CARM1 inhibition by indole and pyrazole inhibitors

2011 ◽  
Vol 436 (2) ◽  
pp. 331-339 ◽  
Author(s):  
John S. Sack ◽  
Sandrine Thieffine ◽  
Tiziano Bandiera ◽  
Marina Fasolini ◽  
Gerald J. Duke ◽  
...  
Keyword(s):  
Hormone Receptors ◽  
Catalytic Domain ◽  
Multiple Roles ◽  
Structural Basis ◽  
Titration Calorimetry ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Binding Cavity ◽  
Arginine Residues ◽  
Substrate Proteins

CARM1 (co-activator-associated arginine methyltransferase 1) is a PRMT (protein arginine N-methyltransferase) family member that catalyses the transfer of methyl groups from SAM (S-adenosylmethionine) to the side chain of specific arginine residues of substrate proteins. This post-translational modification of proteins regulates a variety of transcriptional events and other cellular processes. Moreover, CARM1 is a potential oncological target due to its multiple roles in transcription activation by nuclear hormone receptors and other transcription factors such as p53. Here, we present crystal structures of the CARM1 catalytic domain in complex with cofactors [SAH (S-adenosyl-L-homocysteine) or SNF (sinefungin)] and indole or pyazole inhibitors. Analysis of the structures reveals that the inhibitors bind in the arginine-binding cavity and the surrounding pocket that exists at the interface between the N- and C-terminal domains. In addition, we show using ITC (isothermal titration calorimetry) that the inhibitors bind to the CARM1 catalytic domain only in the presence of the cofactor SAH. Furthermore, sequence differences for select residues that interact with the inhibitors may be responsible for the CARM1 selectivity against PRMT1 and PRMT3. Together, the structural and biophysical information should aid in the design of both potent and specific inhibitors of CARM1.

The roles of peptidyl-proline isomerases in gene regulation1This review is part of Special Issue entitled Asilomar Chromatin and has undergone the Journal’s usual peer review process.

2012 ◽  
Vol 90 (1) ◽  
pp. 55-69 ◽  
Author(s):  
David Dilworth ◽  
Geoff Gudavicius ◽  
Andrew Leung ◽  
Christopher J. Nelson
Keyword(s):  
Protein Function ◽  
Peer Review Process ◽  
Post Translational Modification ◽  
Multiple Control ◽  
Proline Isomerization ◽  
Evolutionarily Conserved ◽  
Covalent Modifications ◽  
And Function ◽  
Fk506 Binding Proteins ◽  
Substrate Proteins

The post-translational modification of proteins and enzymes provides a dynamic and reversible means to control protein function and transmit biological signals. While covalent modifications such as phosphorylation and acetylation have drawn much attention, in the past decade the involvement of peptidyl-proline isomerases (PPIs) in signaling and post-translational modification of protein function has become increasingly apparent. Three distinct families of PPI enzymes (parvulins, cyclophilins, and FK506-binding proteins (FKBPs)) each have the capacity to catalyze cis–trans proline isomerization in substrate proteins, and this modification can regulate both structure and function. In eukaryotic cells, a subset of these enzymes is localized to the nucleus, where they regulate gene expression at multiple control points. Here we summarize this body of work that together establishes a clear role of these enzymes as evolutionarily conserved players in the control of both transcription of mRNAs and the assembly of chromatin.

scholarly journals Human Cytomegalovirus Protein pp71 Induces Daxx SUMOylation

2009 ◽  
Vol 83 (13) ◽  
pp. 6591-6598 ◽  
Author(s):  
Jiwon Hwang ◽  
Robert F. Kalejta
Keyword(s):  
Gene Expression ◽  
Human Cytomegalovirus ◽  
Protein Function ◽  
Viral Infections ◽  
Biological Significance ◽  
Qualitative Change ◽  
Nuclear Bodies ◽  
Cellular Processes ◽  
Unknown Protein ◽  
Lysine Residues

ABSTRACT Proteins that participate in a diverse array of cellular processes can be modified covalently and reversibly on lysine residues by the small ubiquitin-like modifier proteins termed SUMOs. In some instances, such modification profoundly affects protein function, but the biological significance of many SUMOylation events remains unknown. Protein SUMOylation is modulated during many viral infections. Here we demonstrate that the human cytomegalovirus (HCMV) pp71 protein promotes the SUMOylation of its cellular substrate, Daxx. A component of promyelocytic leukemia nuclear bodies, Daxx is a transcriptional corepressor that silences the expression of viral immediate-early (IE) genes at the start of both lytic and quiescent HCMV infections. pp71 is a tegument component delivered directly to cells by infecting HCMV virions. At the start of lytic infections, it travels to the nucleus and stimulates viral IE gene expression by displacing the chromatin remodeling protein ATRX from Daxx and by mediating Daxx degradation through a rare ubiquitin-independent, proteasome-dependent process. Here we report that pp71 also substantially increases the basal level of SUMOylated Daxx observed in cells. To date, consequences of Daxx SUMOylation have not been observed for cellular promoters, and we detected no qualitative change in viral IE gene expression in the absence of pp71-induced Daxx SUMOylation. Thus, while pp71 enhances the basal level of SUMOylated Daxx, the role that this modification plays in regulating Daxx activity in uninfected or HCMV-infected cells remains an enigma.

scholarly journals Systematic approaches to identify E3 ligase substrates

2016 ◽  
Vol 473 (22) ◽  
pp. 4083-4101 ◽  
Author(s):  
Mary Iconomou ◽  
Darren N. Saunders
Keyword(s):  
Cell Cycle Progression ◽  
Target Identification ◽  
Ubiquitin Proteasome System ◽  
Model Systems ◽  
Covalent Attachment ◽  
Post Translational Modification ◽  
Diverse Range ◽  
E3 Ligases ◽  
Ubiquitin Proteasome ◽  
Substrate Proteins

Protein ubiquitylation is a widespread post-translational modification, regulating cellular signalling with many outcomes, such as protein degradation, endocytosis, cell cycle progression, DNA repair and transcription. E3 ligases are a critical component of the ubiquitin proteasome system (UPS), determining the substrate specificity of the cascade by the covalent attachment of ubiquitin to substrate proteins. Currently, there are over 600 putative E3 ligases, but many are poorly characterized, particularly with respect to individual protein substrates. Here, we highlight systematic approaches to identify and validate UPS targets and discuss how they are underpinning rapid advances in our understanding of the biochemistry and biology of the UPS. The integration of novel tools, model systems and methods for target identification is driving significant interest in drug development, targeting various aspects of UPS function and advancing the understanding of a diverse range of disease processes.

scholarly journals Orphan Macrodomain Protein (Human C6orf130) Is an O-Acyl-ADP-ribose Deacylase

2011 ◽  
Vol 286 (41) ◽  
pp. 35955-35965 ◽  
Author(s):  
Francis C. Peterson ◽  
Dawei Chen ◽  
Betsy L. Lytle ◽  
Marianna N. Rossi ◽  
Ivan Ahel ◽  
...  
Keyword(s):  
Catalytic Mechanism ◽  
Amino Acid Residues ◽  
Post Translational Modification ◽  
Phylogenic Tree ◽  
Cellular Processes ◽  
Steady State Kinetic ◽  
Lysine Residues ◽  
Binding Cleft ◽  
And Function ◽  
State Kinetic

Post-translational modification of proteins/histones by lysine acylation has profound effects on the physiological function of modified proteins. Deacylation by NAD+-dependent sirtuin reactions yields as a product O-acyl-ADP-ribose, which has been implicated as a signaling molecule in modulating cellular processes. Macrodomain-containing proteins are reported to bind NAD+-derived metabolites. Here, we describe the structure and function of an orphan macrodomain protein, human C6orf130. This unique 17-kDa protein is a stand-alone macrodomain protein that occupies a distinct branch in the phylogenic tree. We demonstrate that C6orf130 catalyzes the efficient deacylation of O-acetyl-ADP-ribose, O-propionyl-ADP-ribose, and O-butyryl-ADP-ribose to produce ADP-ribose (ADPr) and acetate, propionate, and butyrate, respectively. Using NMR spectroscopy, we solved the structure of C6orf130 in the presence and absence of ADPr. The structures showed a canonical fold with a deep ligand (ADPr)-binding cleft. Structural comparisons of apo-C6orf130 and the ADPr-C6orf130 complex revealed fluctuations of the β5-α4 loop that covers the bound ADPr, suggesting that the β5-α4 loop functions as a gate to sequester substrate and offer flexibility to accommodate alternative substrates. The ADPr-C6orf130 complex identified amino acid residues involved in substrate binding and suggested residues that function in catalysis. Site-specific mutagenesis and steady-state kinetic analyses revealed two critical catalytic residues, Ser-35 and Asp-125. We propose a catalytic mechanism for deacylation of O-acyl-ADP-ribose by C6orf130 and discuss the biological implications in the context of reversible protein acylation at lysine residues.

Sign in / Sign up

Export Citation Format

Share Document