scholarly journals Omic-Sig: Utilizing Omics Data to Explore and Visualize Kinase-Substrate Interactions

2019 ◽  
Author(s):  
T. Mamie Lih ◽  
David J. Clark ◽  
Hui Zhang
Keyword(s):  
Protein Phosphorylation ◽  
Software Tool ◽  
Omics Data ◽  
Additional Insight ◽  
Post Translational Modifications ◽  
Kinase Substrate ◽  
Cellular Processes ◽  
Visualization Software ◽  
And Control ◽  
Insight Into

AbstractProtein phosphorylation is one of the most prevalent post-translational modifications, resulting from the activity of protein kinases phosphorylating specific substrates. Multiple cellular processes are regulated via protein phosphorylation, with aberrant signaling driven by dysregulation of phosphorylation events and associating with disease progression (e.g., cancer). Mass spectrometry-based phosphoprotomics approaches can be leveraged for studying alterations of kinase-substrate activity in clinical cohorts. However, the information gained via interrogation of global proteomes and transcriptomes can offer additional insight into the interaction of kinases and their respective substrates. Therefore, we have developed the bioinformatics, data visualization software tool, Omic-Sig, which can stratify prominent phospho-substrates and their associated kinases based on differential abundances between case and control samples (e.g., tumors and their normal adjacent tissues from a cancer cohort) in a multi-omics fashion. Omic-Sig is available at https://github.com/hzhangjhu/Omic-Sig.

Lysine modifications and autophagy

2012 ◽  
Vol 52 ◽  
pp. 65-77 ◽  
Author(s):  
Kristi L. Norris ◽  
Tso-Pang Yao
Keyword(s):  
Cellular Stress ◽  
Nutrient Deprivation ◽  
Substrate Selectivity ◽  
Catabolic Pathway ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Lysine Residues ◽  
Clinical Potential ◽  
Insight Into

Nutrient deprivation or cellular stress leads to the activation of a catabolic pathway that is conserved across species, known as autophagy. This process is considered to be adaptive and plays an important role in a number of cellular processes, including metabolism, immunity and development. Autophagy has also been linked to diseases, such as cancer and neurodegeneration, highlighting the importance of a better insight into its regulation. In the present chapter, we discuss how PTMs (post-translational modifications) of lysine residues by acetylation and ubiquitination alter the function of key proteins involved in the activation, maturation and substrate selectivity of autophagy. We also discuss the clinical potential of targeting these modifications to modulate autophagic activities.

scholarly journals Integrating bioinformatics tools to investigate protein phosphorylation

2015 ◽  
Author(s):  
Dimitrios Vlachakis ◽  
Elena Bencurova ◽  
Mangesh Bhide ◽  
Sophia Kossida
Keyword(s):  
Mass Spectrometry ◽  
Western Blot ◽  
Protein Phosphorylation ◽  
Gel Electrophoresis ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Phosphorylation Sites ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Benchmark Study

Protein phosphorylation is one of the most important protein post-translational modifications and plays a role in numerous cellular processes including recognition, signaling and degradation. It can be studied experimentally by various methodologies, like employing western blot analysis, site-directed mutagenesis, 2 D gel electrophoresis, mass spectrometry etc. A number of in silico tools have also been developed in order to predict plausible phosphorylation sites in a given protein. In this review, we conducted a benchmark study including the leading protein phosphorylation prediction software, in an effort to determine which performs best. The first place was taken by GPS 2.2, having predicted all phosphorylation sites with a 83% fidelity while in second place came NetPhos 2.0 with 69%.

scholarly journals Specific lid-base contacts in the 26S proteasome control the conformational switching required for substrate engagement and degradation

2019 ◽  
Author(s):  
Eric R. Greene ◽  
Ellen A. Goodall ◽  
Andres H. de la Peña ◽  
Mary E. Matyskiela ◽  
Gabriel C. Lander ◽  
...  
Keyword(s):  
Conformational Changes ◽  
26S Proteasome ◽  
Conformational Switching ◽  
Atpase Subunit ◽  
Aaa Atpase ◽  
Cellular Processes ◽  
Substrate Processing ◽  
And Control ◽  
Early Degradation ◽  
Insight Into

AbstractThe 26S proteasome is essential for protein homeostasis and the regulation of vital cellular processes through ATP-dependent degradation of ubiquitinated substrates. To accomplish the multi-step reaction of protein degradation, the proteasome’s regulatory particle, consisting of the lid and base subcomplexes, undergoes major conformational changes whose origin and control are largely unknown. Investigating the Saccharomyces cerevisiae 26S proteasome, we found that peripheral interactions between the lid subunit Rpn5 and the base AAA+ ATPase ring play critical roles in stabilizing the substrate-engagement-competent state and coordinating the conformational switch to processing states after a substrate has been engaged. Disrupting these interactions perturbs the conformational equilibrium and interferes with degradation initiation, while later steps of substrate processing remain unaffected. Similar defects in the early degradation steps are also observed when eliminating hydrolysis in the ATPase subunit Rpt6, whose nucleotide state seems to control conformational transitions of the proteasome. These results provide important insight into the network of interactions that coordinate conformational changes with various stages of proteasomal degradation, and how modulators of conformational equilibria may influence substrate turnover.

The regulation of protein phosphorylation

2009 ◽  
Vol 37 (4) ◽  
pp. 627-641 ◽  
Author(s):  
Louise N. Johnson
Keyword(s):  
Protein Phosphorylation ◽  
Protein Kinases ◽  
Drug Targets ◽  
Cell Cycle Progression ◽  
Catalytic Domain ◽  
Cell Movement ◽  
Cellular Processes ◽  
Cell Life ◽  
Diseased State ◽  
And Control

Phosphorylation plays essential roles in nearly every aspect of cell life. Protein kinases regulate signalling pathways and cellular processes that mediate metabolism, transcription, cell-cycle progression, differentiation, cytoskeleton arrangement and cell movement, apoptosis, intercellular communication, and neuronal and immunological functions. Protein kinases share a conserved catalytic domain, which catalyses the transfer of the γ-phosphate of ATP to a serine, threonine or tyrosine residue in protein substrates. The kinase can exist in an active or inactive state regulated by a variety of mechanisms in different kinases that include control by phosphorylation, regulation by additional domains that may target other molecules, binding and regulation by additional subunits, and control by protein–protein association. This Novartis Medal Lecture was delivered at a meeting on protein evolution celebrating the 200th anniversary of Charles Darwin's birth. I begin with a summary of current observations from protein sequences of kinase phylogeny. I then review the structural consequences of protein phosphorylation using our work on glycogen phosphorylase to illustrate one of the more dramatic consequences of phosphorylation. Regulation of protein phosphorylation is frequently disrupted in the diseased state, and protein kinases have become high-profile targets for drug development. Finally, I consider recent advances on protein kinases as drug targets and describe some of our recent work with CDK9 (cyclin-dependent kinase 9)–cyclin T, a regulator of transcription.

scholarly journals Integrating bioinformatics tools to investigate protein phosphorylation

2015 ◽  
Author(s):  
Dimitrios Vlachakis ◽  
Elena Bencurova ◽  
Mangesh Bhide ◽  
Sophia Kossida
Keyword(s):  
Mass Spectrometry ◽  
Western Blot ◽  
Protein Phosphorylation ◽  
Gel Electrophoresis ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Phosphorylation Sites ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Benchmark Study

Protein phosphorylation is one of the most important protein post-translational modifications and plays a role in numerous cellular processes including recognition, signaling and degradation. It can be studied experimentally by various methodologies, like employing western blot analysis, site-directed mutagenesis, 2 D gel electrophoresis, mass spectrometry etc. A number of in silico tools have also been developed in order to predict plausible phosphorylation sites in a given protein. In this review, we conducted a benchmark study including the leading protein phosphorylation prediction software, in an effort to determine which performs best. The first place was taken by GPS 2.2, having predicted all phosphorylation sites with a 83% fidelity while in second place came NetPhos 2.0 with 69%.

Reading the phosphorylation code: binding of the 14-3-3 protein to multivalent client phosphoproteins

2020 ◽  
Vol 477 (7) ◽  
pp. 1219-1225 ◽  
Author(s):  
Nikolai N. Sluchanko
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Protein ◽  
Structural Basis ◽  
Major Protein ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Biochemical Journal ◽  
Multiple Binding ◽  
And Control

Many major protein–protein interaction networks are maintained by ‘hub’ proteins with multiple binding partners, where interactions are often facilitated by intrinsically disordered protein regions that undergo post-translational modifications, such as phosphorylation. Phosphorylation can directly affect protein function and control recognition by proteins that ‘read’ the phosphorylation code, re-wiring the interactome. The eukaryotic 14-3-3 proteins recognizing multiple phosphoproteins nicely exemplify these concepts. Although recent studies established the biochemical and structural basis for the interaction of the 14-3-3 dimers with several phosphorylated clients, understanding their assembly with partners phosphorylated at multiple sites represents a challenge. Suboptimal sequence context around the phosphorylated residue may reduce binding affinity, resulting in quantitative differences for distinct phosphorylation sites, making hierarchy and priority in their binding rather uncertain. Recently, Stevers et al. [Biochemical Journal (2017) 474: 1273–1287] undertook a remarkable attempt to untangle the mechanism of 14-3-3 dimer binding to leucine-rich repeat kinase 2 (LRRK2) that contains multiple candidate 14-3-3-binding sites and is mutated in Parkinson's disease. By using the protein-peptide binding approach, the authors systematically analyzed affinities for a set of LRRK2 phosphopeptides, alone or in combination, to a 14-3-3 protein and determined crystal structures for 14-3-3 complexes with selected phosphopeptides. This study addresses a long-standing question in the 14-3-3 biology, unearthing a range of important details that are relevant for understanding binding mechanisms of other polyvalent proteins.

Classification of Infant Vocalizations by Untrained Listeners

2019 ◽  
Vol 62 (9) ◽  
pp. 3265-3275
Author(s):  
Heather L. Ramsdell-Hudock ◽  
Anne S. Warlaumont ◽  
Lindsey E. Foss ◽  
Candice Perry
Keyword(s):  
Formal Education ◽  
Additional Insight ◽  
Listener Responses ◽  
Infant Vocalization ◽  
Early Infant ◽  
Infant Vocalizations ◽  
Audio Recordings ◽  
Speech And Language Development ◽  
Insight Into

Purpose To better enable communication among researchers, clinicians, and caregivers, we aimed to assess how untrained listeners classify early infant vocalization types in comparison to terms currently used by researchers and clinicians. Method Listeners were caregivers with no prior formal education in speech and language development. A 1st group of listeners reported on clinician/researcher-classified vowel, squeal, growl, raspberry, whisper, laugh, and cry vocalizations obtained from archived video/audio recordings of 10 infants from 4 through 12 months of age. A list of commonly used terms was generated based on listener responses and the standard research terminology. A 2nd group of listeners was presented with the same vocalizations and asked to select terms from the list that they thought best described the sounds. Results Classifications of the vocalizations by listeners largely overlapped with published categorical descriptors and yielded additional insight into alternate terms commonly used. The biggest discrepancies were found for the vowel category. Conclusion Prior research has shown that caregivers are accurate in identifying canonical babbling, a major prelinguistic vocalization milestone occurring at about 6–7 months of age. This indicates that caregivers are also well attuned to even earlier emerging vocalization types. This supports the value of continuing basic and clinical research on the vocal types infants produce in the 1st months of life and on their potential diagnostic utility, and may also help improve communication between speech-language pathologists and families.

An insight into Case Management and Challenges in Veteran Suicide Prevention

2020 ◽  
pp. 14-25
Author(s):  
Tamara Green
Keyword(s):  
Case Management ◽  
Suicide Prevention ◽  
Suicide Risk ◽  
Digital Transformation ◽  
Prevention Science ◽  
Historical Records ◽  
Military Members ◽  
Prediction And Control ◽  
And Control ◽  
Insight Into

Much of the literature, policies, programs, and investment has been made on mental health, case management, and suicide prevention of veterans. The Australian “veteran community is facing a suicide epidemic for the reasons that are extremely complex and beyond the scope of those currently dealing with them.” (Menz, D: 2019). Only limited work has considered the digital transformation of loosely and manual-based historical records and no enablement of Artificial Intelligence (A.I) and machine learning to suicide risk prediction and control for serving military members and veterans to date. This paper presents issues and challenges in suicide prevention and management of veterans, from the standing of policymakers to stakeholders, campaigners of veteran suicide prevention, science and big data, and an opportunity for the digital transformation of case management.

Unrestrictive protein modification localization and quality control for open search of mass spectra

2018 ◽  
Author(s):  
Zhiwu An ◽  
Fuzhou Gong ◽  
Yan Fu
Keyword(s):  
Mass Spectrometry ◽  
Quality Control ◽  
Tandem Mass Spectrometry ◽  
Mass Spectra ◽  
Protein Modification ◽  
Software Tool ◽  
Tandem Mass ◽  
Simulation Data ◽  
Post Translational Modifications

We have developed PTMiner, a first software tool for automated, confident filtering, localization and annotation of protein post-translational modifications identified by open (mass-tolerant) search of large tandem mass spectrometry datasets. The performance of the software was validated on carefully designed simulation data. <br>

Diversity, Rationality, and the Division of Cognitive Labor

2017 ◽  
Author(s):  
Ryan Muldoon
Keyword(s):  
Social Structure ◽  
Division Of Labor ◽  
Additional Insight ◽  
Division Of Cognitive Labor ◽  
Social Structure Of Science ◽  
The Social ◽  
Insight Into

Existing models of the division of cognitive labor in science assume that scientists have a particular problem they want to solve and can choose between different approaches to solving the problem. In this essay I invert the approach, supposing that scientists have fixed skills and seek problems to solve. This allows for a better explanation of increasing rates of cooperation in science, as well as flows of scientists between fields of inquiry. By increasing the realism of the model, we gain additional insight into the social structure of science and gain the ability to ask new questions about the optimal division of labor.

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