scholarly journals DegSampler: Gibbs sampling strategy for predicting E3-binding sites with position-specific prior information

2020 ◽  
Author(s):  
Osamu Maruyama ◽  
Fumiko Matsuzaki
Keyword(s):  
Gibbs Sampling ◽  
Binding Sites ◽  
Motif Discovery ◽  
Sampling Strategy ◽  
Ubiquitin Proteasome System ◽  
Cellular Processes ◽  
Substrate Protein ◽  
Region Data ◽  
Gibbs Sampling Algorithm ◽  
Substrate Proteins

Abstract Background: The ubiquitin-proteasome system is a pathway in eukaryotic cells for degrading polyubiquitin-tagged proteins through the proteasomal machinery to control various cellular processes and maintain intracellular homeostasis. In this system, the E3 ubiquitin ligase (hereinafter E3) plays an important role in selectively recognizing and binding to specific regions of its substrate proteins. The relationship between a substrate protein and its sites bound by E3s is not well understood. Thus, it is challenging to computationally identify such sites in substrate proteins. Results: In this study, we proposed a collapsed Gibbs sampling algorithm called DegSampler (Degron Sampler) to identify the binding sites of E3s. DegSampler employs a position-specific prior probability distribution, based on the estimated information of the disorder-to-order region bound by any protein. Conclusions: Our computational experiments show that DegSampler achieved 5 and 3.5 times higher the F-measure values of MEME and GLAM2, respectively. Thus DegSampler is the first model demonstrating an effective way of using estimated information on disorder-to-order binding regions in motif discovery. We expect our results to improve further as higher quality proteome-wide disorder-to-order binding region data become available.

scholarly journals The Effect of Dysfunctional Ubiquitin Enzymes in the Pathogenesis of Most Common Diseases

2020 ◽  
Vol 21 (17) ◽  
pp. 6335 ◽  
Author(s):  
Gizem Celebi ◽  
Hale Kesim ◽  
Ebru Ozer ◽  
Ozlem Kutlu
Keyword(s):  
Protein Quality ◽  
Ubiquitin Proteasome System ◽  
Deubiquitinating Enzymes ◽  
E3 Ligases ◽  
Substrate Protein ◽  
Common Diseases ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Conjugating Enzymes ◽  
Substrate Proteins

Ubiquitination is a multi-step enzymatic process that involves the marking of a substrate protein by bonding a ubiquitin and protein for proteolytic degradation mainly via the ubiquitin–proteasome system (UPS). The process is regulated by three main types of enzymes, namely ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). Under physiological conditions, ubiquitination is highly reversible reaction, and deubiquitinases or deubiquitinating enzymes (DUBs) can reverse the effect of E3 ligases by the removal of ubiquitin from substrate proteins, thus maintaining the protein quality control and homeostasis in the cell. The dysfunction or dysregulation of these multi-step reactions is closely related to pathogenic conditions; therefore, understanding the role of ubiquitination in diseases is highly valuable for therapeutic approaches. In this review, we first provide an overview of the molecular mechanism of ubiquitination and UPS; then, we attempt to summarize the most common diseases affecting the dysfunction or dysregulation of these mechanisms.

scholarly journals Recognition and targeting mechanisms by chaperones in flagellum assembly and operation

2016 ◽  
Vol 113 (35) ◽  
pp. 9798-9803 ◽  
Author(s):  
Nandish Khanra ◽  
Paolo Rossi ◽  
Anastassios Economou ◽  
Charalampos G. Kalodimos
Keyword(s):  
Membrane Protein ◽  
Binding Sites ◽  
Solution Structure ◽  
Hydrophobic Surface ◽  
The Other ◽  
Capping Protein ◽  
Substrate Complex ◽  
Substrate Protein ◽  
Flagellar Proteins ◽  
Substrate Proteins

The flagellum is a complex bacterial nanomachine that requires the proper assembly of several different proteins for its function. Dedicated chaperones are central in preventing aggregation or undesired interactions of flagellar proteins, including their targeting to the export gate. FliT is a key flagellar chaperone that binds to several flagellar proteins in the cytoplasm, including its cognate filament-capping protein FliD. We have determined the solution structure of the FliT chaperone in the free state and in complex with FliD and the flagellar ATPase FliI. FliT adopts a four-helix bundle and uses a hydrophobic surface formed by the first three helices to recognize its substrate proteins. We show that the fourth helix constitutes the binding site for FlhA, a membrane protein at the export gate. In the absence of a substrate protein FliT adopts an autoinhibited structure wherein both the binding sites for substrates and FlhA are occluded. Substrate binding to FliT activates the complex for FlhA binding and thus targeting of the chaperone–substrate complex to the export gate. The activation and targeting mechanisms reported for FliT appear to be shared among the other flagellar chaperones.

E3 ubiquitin ligases

2005 ◽  
Vol 41 ◽  
pp. 15-30 ◽  
Author(s):  
Helen C. Ardley ◽  
Philip A. Robinson
Keyword(s):  
Protein Complexes ◽  
Loss Of Function ◽  
Direct Role ◽  
Cellular Processes ◽  
Substrate Protein ◽  
Protein Ubiquitination ◽  
C Terminus ◽  
Full Complement ◽  
Spatio Temporal ◽  
Eukaryotic Organisms

The selectivity of the ubiquitin–26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin–protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.

scholarly journals A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1929
Author(s):  
Eva M. Huber ◽  
Michael Groll
Keyword(s):  
Cell Cycle Progression ◽  
Therapeutic Potential ◽  
Cell Signalling ◽  
Selective Inhibition ◽  
Ubiquitin Proteasome System ◽  
Cellular Processes ◽  
Chemical Structures ◽  
Phase Ii Clinical Trials ◽  
Ubiquitin Proteasome ◽  
Recent Trends

At the heart of the ubiquitin–proteasome system, the 20S proteasome core particle (CP) breaks down the majority of intracellular proteins tagged for destruction. Thereby, the CP controls many cellular processes including cell cycle progression and cell signalling. Inhibitors of the CP can suppress these essential biological pathways, resulting in cytotoxicity, an effect that is beneficial for the treatment of certain blood cancer patients. During the last decade, several preclinical studies demonstrated that selective inhibition of the immunoproteasome (iCP), one of several CP variants in mammals, suppresses autoimmune diseases without inducing toxic side effects. These promising findings led to the identification of natural and synthetic iCP inhibitors with distinct chemical structures, varying potency and subunit selectivity. This review presents the most prominent iCP inhibitors with respect to possible scientific and medicinal applications, and discloses recent trends towards pan-immunoproteasome reactive inhibitors that cumulated in phase II clinical trials of the lead compound KZR-616 for chronic inflammations.

scholarly journals Ubiquitin and Ubiquitin-Like Proteins and Domains in Ribosome Production and Function: Chance or Necessity?

2021 ◽  
Vol 22 (9) ◽  
pp. 4359
Author(s):  
Sara Martín-Villanueva ◽  
Gabriel Gutiérrez ◽  
Dieter Kressler ◽  
Jesús de la Cruz
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Ribosome Assembly ◽  
Cellular Processes ◽  
Substrate Protein ◽  
Precursor Proteins ◽  
Assembly Factors ◽  
Ubiquitin Moiety ◽  
And Function

Ubiquitin is a small protein that is highly conserved throughout eukaryotes. It operates as a reversible post-translational modifier through a process known as ubiquitination, which involves the addition of one or several ubiquitin moieties to a substrate protein. These modifications mark proteins for proteasome-dependent degradation or alter their localization or activity in a variety of cellular processes. In most eukaryotes, ubiquitin is generated by the proteolytic cleavage of precursor proteins in which it is fused either to itself, constituting a polyubiquitin precursor, or as a single N-terminal moiety to ribosomal proteins, which are practically invariably eL40 and eS31. Herein, we summarize the contribution of the ubiquitin moiety within precursors of ribosomal proteins to ribosome biogenesis and function and discuss the biological relevance of having maintained the explicit fusion to eL40 and eS31 during evolution. There are other ubiquitin-like proteins, which also work as post-translational modifiers, among them the small ubiquitin-like modifier (SUMO). Both ubiquitin and SUMO are able to modify ribosome assembly factors and ribosomal proteins to regulate ribosome biogenesis and function. Strikingly, ubiquitin-like domains are also found within two ribosome assembly factors; hence, the functional role of these proteins will also be highlighted.

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.

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