SUMO and ubiquitin paths converge

2010 ◽  
Vol 38 (1) ◽  
pp. 34-39 ◽  
Author(s):  
Amanda Denuc ◽  
Gemma Marfany
Keyword(s):  
Genome Stability ◽  
Cell Signalling ◽  
Covalent Attachment ◽  
Small Peptides ◽  
Protein Activity ◽  
Protein Protein Interaction ◽  
Cellular Processes ◽  
Reversible Covalent ◽  
And Function

One of the more rapidly expanding fields in cell signalling nowadays is the characterization of proteins conjugated to Ub (ubiquitin) or Ub-like peptides, such as SUMO (small Ub-related modifier). The reversible covalent attachment of these small peptides remodels the target protein, providing new protein–protein interaction interfaces, which can be dynamically regulated given a set of enzymes for conjugation and deconjugation. First, ubiquitination was thought to be merely relegated to the control of protein turnover and degradation, whereas the attachment of SUMO was involved in the regulation of protein activity and function. However, the boundaries between the protein fates related to these tag molecules are becoming more and more fuzzy, as either the differences between mono-, multi- and poly-modifications or the lysine residue used for growth of the poly-chains is being dissected. The Ub and SUMO pathways are no longer separated, and many examples of this cross-talk are found in the literature, involving different cellular processes ranging from DNA repair and genome stability, to the regulation of protein subcellular localization or enzyme activity. Here, we review several cases in which SUMOylation and ubiquitination intersect, showing also that the same protein can be conjugated to SUMO and Ub for antagonistic, synergistic or multiple outcomes, illustrating the intricacy of the cellular signalling networks. Ub and SUMO have met and are now applying for new regulatory roles in the cell.

scholarly journals Heterochromatin: Guardian of the Genome

2018 ◽  
Vol 34 (1) ◽  
pp. 265-288 ◽  
Author(s):  
Aniek Janssen ◽  
Serafin U. Colmenares ◽  
Gary H. Karpen
Keyword(s):  
Chromosome Segregation ◽  
Genome Stability ◽  
Constitutive Heterochromatin ◽  
Repetitive Sequences ◽  
Genome Integrity ◽  
Chromatin Domain ◽  
Cellular Processes ◽  
Eukaryotic Nucleus ◽  
And Function ◽  
Heterochromatin Structure

Constitutive heterochromatin is a major component of the eukaryotic nucleus and is essential for the maintenance of genome stability. Highly concentrated at pericentromeric and telomeric domains, heterochromatin is riddled with repetitive sequences and has evolved specific ways to compartmentalize, silence, and repair repeats. The delicate balance between heterochromatin epigenetic maintenance and cellular processes such as mitosis and DNA repair and replication reveals a highly dynamic and plastic chromatin domain that can be perturbed by multiple mechanisms, with far-reaching consequences for genome integrity. Indeed, heterochromatin dysfunction provokes genetic turmoil by inducing aberrant repeat repair, chromosome segregation errors, transposon activation, and replication stress and is strongly implicated in aging and tumorigenesis. Here, we summarize the general principles of heterochromatin structure and function, discuss the importance of its maintenance for genome integrity, and propose that more comprehensive analyses of heterochromatin roles in tumorigenesis will be integral to future innovations in cancer treatment.

scholarly journals Design of self-assembling transmembrane helical bundles to elucidate principles required for membrane protein folding and ion transport

2017 ◽  
Vol 372 (1726) ◽  
pp. 20160214 ◽  
Author(s):  
Nathan H. Joh ◽  
Gevorg Grigoryan ◽  
Yibing Wu ◽  
William F. DeGrado
Keyword(s):  
Protein Folding ◽  
Membrane Protein ◽  
Protein Design ◽  
De Novo ◽  
Cell Signalling ◽  
Membrane Protein Folding ◽  
Cellular Processes ◽  
Membrane Pores ◽  
Self Assembling ◽  
And Function

Ion transporters and channels are able to identify and act on specific substrates among myriads of ions and molecules critical to cellular processes, such as homeostasis, cell signalling, nutrient influx and drug efflux. Recently, we designed Rocker, a minimalist model for Zn 2+ /H + co-transport. The success of this effort suggests that de novo membrane protein design has now come of age so as to serve a key approach towards probing the determinants of membrane protein folding, assembly and function. Here, we review general principles that can be used to design membrane proteins, with particular reference to helical assemblies with transport function. We also provide new functional and NMR data that probe the dynamic mechanism of conduction through Rocker. This article is part of the themed issue ‘Membrane pores: from structure and assembly, to medicine and technology’.

scholarly journals Label-free methods for optical in vitro characterization of protein–protein interactions

2021 ◽  
Author(s):  
Fabian Soltermann ◽  
Weston B. Struwe ◽  
Philipp Kukura
Keyword(s):  
Protein Interactions ◽  
Label Free ◽  
Protein Protein Interactions ◽  
Cellular Processes ◽  
P Protein ◽  
In Vitro Characterization ◽  
And Function

Protein–protein interactions are involved in the regulation and function of the majority of cellular processes.

scholarly journals Purines as Transmitter Molecules: Electrophysiological Studies on Purinergic Signalling in Different Cell Systems

2009 ◽  
Author(s):  
Elisabetta Coppi
Keyword(s):  
Cell Signalling ◽  
Human Mesenchymal Stem Cells ◽  
Membrane Receptors ◽  
Receptor Expression ◽  
Purinergic Signalling ◽  
Cell Systems ◽  
Cellular Processes ◽  
Electrophysiological Studies ◽  
And Function

Purinergic nucleotides and nucleosides (ATP, ADP, AMP and adenosine) are essential intracellular metabolites involved in a number of cellular processes, from energy supply to protein phosphorylation. However, in the last years, several studies demonstrated their involvement in cell signalling by the activation of specific membrane receptors (P1 and P2) and their role as neurotransmitters began to be investigated. The present work was aimed to clarify the effects of purinergic neurotransmission in different cell systems by using electrophysiological techniques. Relevant results of this research include the observation that P1 and P2 receptors play a deleterious role during "in vitro" ischemia in the rat brain, and the first demonstration of P2 receptor expression and function in a line of adult human mesenchymal stem cells.

scholarly journals PES inhibits human inducible Hsp70 by covalent targeting of cysteine residues in the substrate binding domain

2020 ◽  
pp. jbc.RA120.015440
Author(s):  
Jie Yang ◽  
Weibin Gong ◽  
Si Wu ◽  
Hong Zhang ◽  
Sarah Perrett
Keyword(s):  
Drug Target ◽  
Protein Quality ◽  
Addition Reaction ◽  
Conformational Dynamics ◽  
Covalent Attachment ◽  
Michael Addition Reaction ◽  
Cellular Processes ◽  
Covalent Inhibitors ◽  
And Function ◽  
Substrate Binding Domain

Hsp70 proteins are a family of ancient and conserved chaperones. They play important roles in vital cellular processes, such as protein quality control and the stress response. Hsp70 proteins are a potential drug target for treatment of disease, particularly cancer. PES (2-phenylethynesulfonamide or pifithrin-μ) has been reported to be an inhibitor of Hsp70. However, the mechanism of PES inhibition is still unclear. In this study we found that PES can undergo a Michael addition reaction with Cys-574 and Cys-603 in the SBDα of hHsp70, resulting in covalent attachment of a PES molecule to each Cys residue. We previously showed that glutathionylation of Cys-574 and Cys-603 affects the structure and function of hHsp70. In this study, PES modification showed similar structural and functional effects on hHsp70 to glutathionylation. Further, we found that susceptibility to PES modification is influenced by changes in the conformational dynamics of the SBDα, such as are induced by interaction with adjacent domains, allosteric changes and mutations. This study provides new avenues for development of covalent inhibitors of hHsp70.

scholarly journals Wrestling and Wrapping: A Perspective on SUMO Proteins in Schwann Cells

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1055
Author(s):  
Iman F. Fergani ◽  
Luciana R. Frick
Keyword(s):  
Schwann Cells ◽  
Posttranslational Modifications ◽  
Cellular Localization ◽  
Covalent Attachment ◽  
Protein Protein Interaction ◽  
Cellular Processes ◽  
Schwann Cell Development ◽  
Demyelinating Neuropathies ◽  
Underlying Mechanisms ◽  
Substrate Proteins

Schwann cell development and peripheral nerve myelination are finely orchestrated multistep processes; some of the underlying mechanisms are well described and others remain unknown. Many posttranslational modifications (PTMs) like phosphorylation and ubiquitination have been reported to play a role during the normal development of the peripheral nervous system (PNS) and in demyelinating neuropathies. However, a relatively novel PTM, SUMOylation, has not been studied in these contexts. SUMOylation involves the covalent attachment of one or more small ubiquitin-like modifier (SUMO) proteins to a substrate, which affects the function, cellular localization, and further PTMs of the conjugated protein. SUMOylation also regulates other proteins indirectly by facilitating non-covalent protein–protein interaction via SUMO interaction motifs (SIM). This pathway has important consequences on diverse cellular processes, and dysregulation of this pathway has been reported in several diseases including neurological and degenerative conditions. In this article, we revise the scarce literature on SUMOylation in Schwann cells and the PNS, we propose putative substrate proteins, and we speculate on potential mechanisms underlying the possible involvement of this PTM in peripheral myelination and neuropathies.

scholarly journals Pathogenesis of Mucopolysaccharidoses, an Update

2020 ◽  
Vol 21 (7) ◽  
pp. 2515 ◽  
Author(s):  
Simona Fecarotta ◽  
Antonietta Tarallo ◽  
Carla Damiano ◽  
Nadia Minopoli ◽  
Giancarlo Parenti
Keyword(s):  
Clinical Manifestations ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Cellular Events ◽  
New Information ◽  
New Vision ◽  
And Function ◽  
And Oxidative Stress ◽  
Novel Therapeutic

The recent advancements in the knowledge of lysosomal biology and function have translated into an improved understanding of the pathophysiology of mucopolysaccharidoses (MPSs). The concept that MPS manifestations are direct consequences of lysosomal engorgement with undegraded glycosaminoglycans (GAGs) has been challenged by new information on the multiple biological roles of GAGs and by a new vision of the lysosome as a signaling hub involved in many critical cellular functions. MPS pathophysiology is now seen as the result of a complex cascade of secondary events that lead to dysfunction of several cellular processes and pathways, such as abnormal composition of membranes and its impact on vesicle fusion and trafficking; secondary storage of substrates; impairment of autophagy; impaired mitochondrial function and oxidative stress; dysregulation of signaling pathways. The characterization of this cascade of secondary cellular events is critical to better understand the pathophysiology of MPS clinical manifestations. In addition, some of these pathways may represent novel therapeutic targets and allow for the development of new therapies for these disorders.

scholarly journals A Giant Ubiquitin-conjugating Enzyme Related to IAP Apoptosis Inhibitors

1998 ◽  
Vol 141 (6) ◽  
pp. 1415-1422 ◽  
Author(s):  
Hans-Peter Hauser ◽  
Michael Bardroff ◽  
George Pyrowolakis ◽  
Stefan Jentsch
Keyword(s):  
Covalent Attachment ◽  
Protein Protein Interaction ◽  
Small Proteins ◽  
The Family ◽  
Golgi Compartment ◽  
Ubiquitin Conjugating Enzyme ◽  
Conjugating Enzymes ◽  
And Function ◽  
Ubiquitin Conjugating Enzymes ◽  
Conjugating Enzyme

Ubiquitin-conjugating enzymes (UBC) catalyze the covalent attachment of ubiquitin to target proteins and are distinguished by the presence of a UBC domain required for catalysis. Previously identified members of this enzyme family are small proteins and function primarily in selective proteolysis pathways. Here we describe BRUCE (BIR repeat containing ubiquitin-conjugating enzyme), a giant (528-kD) ubiquitin-conjugating enzyme from mice. BRUCE is membrane associated and localizes to the Golgi compartment and the vesicular system. Remarkably, in addition to being an active ubiquitin-conjugating enzyme, BRUCE bears a baculovirus inhibitor of apoptosis repeat (BIR) motif, which to this date has been exclusively found in apoptosis inhibitors of the IAP-related protein family. The BIR motifs of IAP proteins are indispensable for their anti–cell death activity and are thought to function through protein–protein interaction. This suggests that BRUCE may combine properties of IAP-like proteins and ubiquitin-conjugating enzymes and indicates that the family of IAP-like proteins is structurally and functionally more diverse than previously expected.

scholarly journals Mimicking Strategy for Protein–Protein Interaction Inhibitor Discovery by Virtual Screening

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4428 ◽  
Author(s):  
Ke-Jia Wu ◽  
Pui-Man Lei ◽  
Hao Liu ◽  
Chun Wu ◽  
Chung-Hang Leung ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Cellular Processes ◽  
Promising Strategy ◽  
Protein Partners ◽  
Inhibitor Discovery ◽  
And Function

As protein–protein interactions (PPIs) are highly involved in most cellular processes, the discovery of PPI inhibitors that mimic the structure of the natural protein partners is a promising strategy toward the discovery of PPI inhibitors. In this review, we discuss recent advances in the application of virtual screening for identifying mimics of protein partners. The classification and function of the mimicking protein partner inhibitor discovery by virtual screening are described. We anticipate that this review would be of interest to medicinal chemists and chemical biologists working in the field of protein–protein interaction inhibitors or probes.

scholarly journals Characterization of Protein-Lipid Interactions in Biosystems Processes

2019 ◽  
pp. 93-99
Author(s):  
Dr. Chrysanthus Chukwuma Sr
Keyword(s):  
Membrane Proteins ◽  
Binding Sites ◽  
Systematic Investigation ◽  
Morphological Characterization ◽  
Protein Activity ◽  
Lipid Interactions ◽  
Cellular Processes ◽  
Normal Enzyme ◽  
Basic And Applied Research

Lipids correlate with membrane characteristics and functionalities as macromolecular constituentts in all cellular processes. Numerous aspects of lipid modulation of protein activity and structure are not completely understood and, thus a holistic systematic investigation activities will be pertinent. Protein-lipid interactions are the resultant impacts of membrane proteins on lipid physical states or vice versa. Encompassing research needs to be associated with strategies to elucidate whether proteins contain binding sites which are lipid specific, and that the protein-lipid complexes are ostensibly long-lived, on the time order necessary for the turnover of a normal enzyme. Biological membranes have since been determined as essential ingredients in an expansive array of cellular processes, such as photosynthesis, cell defence, signaling transduction, communication and motility. Therefore, they constitute multiple targets in both basic and applied research. Protein-lipid interactions are becoming increasingly relevant to the morphological characterization of membrane proteins as related to their functionalities. Excepting for simplified models, certain protein-lipid interactions specifically constitute remarkable challenges which require optimum experimental paradigm and design.

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