scholarly journals Towards a systematic map of the functional role of protein phosphorylation

2019 ◽  
Author(s):  
Cristina Viéitez ◽  
Bede P. Busby ◽  
David Ochoa ◽  
André Mateus ◽  
Marco Galardini ◽  
...  
Keyword(s):  
Gene Deletion ◽  
Loss Of Function ◽  
Post Translational Modification ◽  
Systematic Map ◽  
Gene Deletions ◽  
Chemical Genetic ◽  
Cellular Processes ◽  
Growth Profiles ◽  
Functional Relevance ◽  
Almost All

AbstractPhosphorylation is a critical post-translational modification involved in the regulation of almost all cellular processes. However, less than 5% of thousands of recently discovered phosphorylation sites have a known function. Here, we devised a chemical genetic approach to study the functional relevance of phosphorylation in S. cerevisiae. We generated 474 phospho-deficient mutants that, along with the gene deletion library, were screened for fitness in 102 conditions. Of these, 42% exhibited growth phenotypes, suggesting these phosphosites are likely functional. We inferred their function based on the similarity of their growth profiles with that of gene deletions, and validated a subset by thermal proteome profiling and lipidomics. While some phosphomutants showed loss-of-function phenotypes, a higher fraction exhibited phenotypes not seen in the corresponding gene deletion suggestive of a gain-of-function effect. For phosphosites conserved in humans, the severity of the yeast phenotypes is indicative of their human functional relevance. This study provides a roadmap for functionally characterizing phosphorylation in a systematic manner.

Semisynthetic triazoles as an approach in the discovery of Novel Lead Compounds

2021 ◽  
Vol 25 ◽  
Author(s):  
Pedro Alves Bezerra Morais ◽  
Carla Santana Francisco ◽  
Heberth de Paula ◽  
Rayssa Ribeiro ◽  
Mariana Alves Eloy ◽  
...  
Keyword(s):  
Natural Products ◽  
Medicinal Chemistry ◽  
Chemical Space ◽  
Biological Activities ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Modern Drug ◽  
New Chemical Entities ◽  
Almost All ◽  
The 19Th Century

: Historically, the medicinal chemistry is concerned with the approach of organic chemistry to new drug synthesis. Considering the fruitful collections of new molecular entities, the dedicated efforts for medicinal chemistry are rewarding. Planning and search of new and applicable pharmacologic therapies involve the altruistic nature of the scientists. Since the 19th century, notoriously the application of isolated and characterized plant-derived compounds in modern drug discovery and in various stages of clinical development highlight its viability and significance. Natural products influence a broad range of biological processes, covering transcription, translation, and post-translational modification and being effective modulators of almost all basic cellular processes. The research of new chemical entities through “click chemistry” continuously opens up a map for the remarkable exploration of chemical space in towards leading natural products optimization by structure-activity relationship. Finally, here in this review, we expect to gather a broad knowledge involving triazolic natural products derivatives, synthetic routes, structures, and their biological activities.

Exploiting S-nitrosylation for cancer therapy: facts and perspectives

2020 ◽  
Vol 477 (19) ◽  
pp. 3649-3672
Author(s):  
Salvatore Rizza ◽  
Giuseppe Filomeni
Keyword(s):  
Nitric Oxide ◽  
Cancer Biology ◽  
Synthetic Lethality ◽  
Current Knowledge ◽  
Tissue Homeostasis ◽  
Loss Of Function ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Insight Into

S-nitrosylation, the post-translational modification of cysteines by nitric oxide, has been implicated in several cellular processes and tissue homeostasis. As a result, alterations in the mechanisms controlling the levels of S-nitrosylated proteins have been found in pathological states. In the last few years, a role in cancer has been proposed, supported by the evidence that various oncoproteins undergo gain- or loss-of-function modifications upon S-nitrosylation. Here, we aim at providing insight into the current knowledge about the role of S-nitrosylation in different aspects of cancer biology and report the main anticancer strategies based on: (i) reducing S-nitrosylation-mediated oncogenic effects, (ii) boosting S-nitrosylation to stimulate cell death, (iii) exploiting S-nitrosylation through synthetic lethality.

scholarly journals Suboptimal Global Transcriptional Response Increases the Harmful Effects of Loss-of-Function Mutations

2020 ◽  
Author(s):  
Károly Kovács ◽  
Zoltán Farkas ◽  
Djordje Bajić ◽  
Dorottya Kalapis ◽  
Andreea Daraba ◽  
...  
Keyword(s):  
Gene Deletion ◽  
Single Gene ◽  
Transcriptional Response ◽  
Gene Inactivation ◽  
Loss Of Function ◽  
Gene Deletions ◽  
Genomic Expression ◽  
Deleterious Gene ◽  
Functionally Diverse ◽  
Harmful Effects

Abstract The fitness impact of loss-of-function mutations is generally assumed to reflect the loss of specific molecular functions associated with the perturbed gene. Here, we propose that rewiring of the transcriptome upon deleterious gene inactivation is frequently nonspecific and mimics stereotypic responses to external environmental change. Consequently, transcriptional response to gene deletion could be suboptimal and incur an extra fitness cost. Analysis of the transcriptomes of ∼1,500 single-gene deletion Saccharomyces cerevisiae strains supported this scenario. First, most transcriptomic changes are not specific to the deleted gene but are rather triggered by perturbations in functionally diverse genes. Second, gene deletions that alter the expression of dosage-sensitive genes are especially harmful. Third, by elevating the expression level of downregulated genes, we could experimentally mitigate the fitness defect of gene deletions. Our work shows that rewiring of genomic expression upon gene inactivation shapes the harmful effects of mutations.

Disruption of protein function by pathogenic mutations: common and uncommon mechanisms

2019 ◽  
Vol 97 (1) ◽  
pp. 46-57 ◽  
Author(s):  
Mikko Taipale
Keyword(s):  
Protein Function ◽  
Loss Of Function ◽  
Protein Coding ◽  
Cellular Processes ◽  
Coding Regions ◽  
Mendelian Disorders ◽  
Pathogenic Variants ◽  
Disease Mutations ◽  
Protein Folding Pathways ◽  
Almost All

Mutations in protein-coding regions underlie almost all Mendelian disorders, drive tumorigenesis, and contribute to susceptibility to common diseases. Despite the great diversity of diseases that are caused by coding mutations, the cellular processes that affect, and are affected by, pathogenic variants at the molecular level are fundamentally conserved. Experimental and computational approaches have revealed that a substantial fraction of disease mutations are not simple loss-of-function alleles. Rather, these pathogenic variants disrupt protein function in more subtle ways by tuning protein folding pathways, altering subcellular trafficking, interrupting signaling cascades, and rewiring highly connected interaction networks. Focusing mainly on Mendelian disorders, this review discusses the common mechanisms by which deleterious mutations disrupt protein function and how these disruptions can be exploited in the development of novel therapies.

scholarly journals Protein Persulfidation in Plants: Function and Mechanism

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1631
Author(s):  
Peng Wang ◽  
Hua Fang ◽  
Rong Gao ◽  
Weibiao Liao
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Growth And Development ◽  
Protective Mechanism ◽  
Post Translational Modification ◽  
Biochemical Processes ◽  
Cellular Processes ◽  
Growth Development ◽  
Almost All ◽  
And Function

As an endogenous gaseous transmitter, the function of hydrogen sulfide (H2S) has been extensively studied in plants. Once synthesized, H2S may be involved in almost all life processes of plants. Among them, a key route for H2S bioactivity occurs via protein persulfidation, in which process oxidizes cysteine thiol (R-SH) groups into persulfide (R-SSH) groups. This process is thought to underpin a myriad of cellular processes in plants linked to growth, development, stress responses, and phytohormone signaling. Multiple lines of emerging evidence suggest that this redox-based reversible post-translational modification can not only serve as a protective mechanism for H2S in oxidative stress, but also control a variety of biochemical processes through the allosteric effect of proteins. Here, we collate emerging evidence showing that H2S-mediated persulfidation modification involves some important biochemical processes such as growth and development, oxidative stress, phytohormone and autophagy. Additionally, the interaction between persulfidation and S-nitrosylation is also discussed. In this work, we provide beneficial clues for further exploration of the molecular mechanism and function of protein persulfidation in plants in the future.

scholarly journals Conserved phosphorylation hotspots in eukaryotic protein domain families

2018 ◽  
Author(s):  
Marta J. Strumillo ◽  
Michaela Oplová ◽  
Cristina Viéitez ◽  
David Ochoa ◽  
Mohammed Shahraz ◽  
...  
Keyword(s):  
Structural Data ◽  
Protein Domain ◽  
Rrna Processing ◽  
Protein Conformations ◽  
Post Translational Modification ◽  
Functional Studies ◽  
Cellular Processes ◽  
Eukaryotic Species ◽  
Cold Sensitive ◽  
Almost All

AbstractProtein phosphorylation is the best characterized post-translational modification that regulates almost all cellular processes through diverse mechanisms such as changing protein conformations, interactions, and localization. While the inventory for phosphorylation sites across different species has rapidly expanded, their functional role remains poorly investigated. Here, we have combined 537,321 phosphosites from 40 eukaryotic species to identify highly conserved phosphorylation “hotspot” regions within domain families. Mapping these regions onto structural data revealed that they are often found at interfaces, near catalytic residues and tend to harbor functionally important phosphosites. Notably, functional studies of a phospho-deficient mutant in the C-terminal hotspot region within the Ribosomal S11 domain in the yeast ribosomal protein uS11 showed cold-sensitive phenotype and impaired 20S pre-rRNA processing. Altogether, our study identified phosphorylation hotspots for 162 protein domains suggestive of an ancient role for the control of diverse eukaryotic domain families.

scholarly journals The functional landscape of the human phosphoproteome

2019 ◽  
Author(s):  
David Ochoa ◽  
Andrew F. Jarnuczak ◽  
Maja Gehre ◽  
Margaret Soucheray ◽  
Askar A. Kleefeldt ◽  
...  
Keyword(s):  
Protein Function ◽  
Molecular Mechanisms ◽  
State Of The Art ◽  
Functional Score ◽  
Post Translational Modification ◽  
Functional Sites ◽  
Cellular Processes ◽  
Major Bottleneck ◽  
Genomic Scale ◽  
Almost All

AbstractProtein phosphorylation is a key post-translational modification regulating protein function in almost all cellular processes. While tens of thousands of phosphorylation sites have been identified in human cells to date, the extent and functional importance of the phosphoproteome remains largely unknown. Here, we have analyzed 6,801 publicly available phospho-enriched mass spectrometry proteomics experiments, creating a state-of-the-art phosphoproteome containing 119,809 human phosphosites. To prioritize functional sites, 59 features indicative of proteomic, structural, regulatory or evolutionary relevance were integrated into a single functional score using machine learning. We demonstrate how this prioritization identifies regulatory phosphosites across different molecular mechanisms and pinpoint genetic susceptibilities at a genomic scale. Several novel regulatory phosphosites were experimentally validated including a role in neuronal differentiation for phosphosites present in the SWI/SNF SMARCC2 complex member. The scored reference phosphoproteome and its annotations identify the most relevant phosphorylations for a given process or disease addressing a major bottleneck in cell signaling studies.

scholarly journals Ubiquitination in Plant Meiosis: Recent Advances and High Throughput Methods

2021 ◽  
Vol 12 ◽  
Author(s):  
Jamie N. Orr ◽  
Robbie Waugh ◽  
Isabelle Colas
Keyword(s):  
Chromosome Segregation ◽  
High Throughput ◽  
Post Translational Modification ◽  
Scf Complex ◽  
Cellular Processes ◽  
Recent Advances ◽  
Expression Of Genes ◽  
Almost All ◽  
Plant Meiosis

Meiosis is a specialized cell division which is essential to sexual reproduction. The success of this highly ordered process involves the timely activation, interaction, movement, and removal of many proteins. Ubiquitination is an extraordinarily diverse post-translational modification with a regulatory role in almost all cellular processes. During meiosis, ubiquitin localizes to chromatin and the expression of genes related to ubiquitination appears to be enhanced. This may be due to extensive protein turnover mediated by proteasomal degradation. However, degradation is not the only substrate fate conferred by ubiquitination which may also mediate, for example, the activation of key transcription factors. In plant meiosis, the specific roles of several components of the ubiquitination cascade—particularly SCF complex proteins, the APC/C, and HEI10—have been partially characterized indicating diverse roles in chromosome segregation, recombination, and synapsis. Nonetheless, these components remain comparatively poorly understood to their counterparts in other processes and in other eukaryotes. In this review, we present an overview of our understanding of the role of ubiquitination in plant meiosis, highlighting recent advances, remaining challenges, and high throughput methods which may be used to overcome them.

scholarly journals A modular toolbox to generate complex polymeric ubiquitin architectures using orthogonal sortase enzymes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maximilian Fottner ◽  
Maria Weyh ◽  
Stefan Gaussmann ◽  
Dominic Schwarz ◽  
Michael Sattler ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cellular Proteins ◽  
Post Translational Modification ◽  
Functional Impact ◽  
Target Proteins ◽  
Cellular Processes ◽  
Damage Repair ◽  
Powerful Approach ◽  
Almost All ◽  
Stepwise Assembly

AbstractThe post-translational modification of proteins with ubiquitin (Ub) and Ub-like modifiers (Ubls) represents one of the most important regulators in eukaryotic biology. Polymeric Ub/Ubl chains of distinct topologies control the activity, stability, interaction and localization of almost all cellular proteins and elicit a variety of biological outputs. Our ability to characterize the roles of distinct Ub/Ubl topologies and to identify enzymes and receptors that create, recognize and remove these modifications is however hampered by the difficulty to prepare them. Here we introduce a modular toolbox (Ubl-tools) that allows the stepwise assembly of Ub/Ubl chains in a flexible and user-defined manner facilitated by orthogonal sortase enzymes. We demonstrate the universality and applicability of Ubl-tools by generating distinctly linked Ub/Ubl hybrid chains, and investigate their role in DNA damage repair. Importantly, Ubl-tools guarantees straightforward access to target proteins, site-specifically modified with distinct homo- and heterotypic (including branched) Ub chains, providing a powerful approach for studying the functional impact of these complex modifications on cellular processes.

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.

Sign in / Sign up

Export Citation Format

Share Document