scholarly journals An optimized optogenetic clustering tool for probing protein interaction and function

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Amir Taslimi ◽  
Justin D. Vrana ◽  
Daniel Chen ◽  
Sofya Borinskaya ◽  
Bruce J. Mayer ◽  
...  
Keyword(s):  
Protein Interaction ◽  
And Function

scholarly journals Classification of Nonenzymatic Homologues of Protein Kinases

2009 ◽  
Vol 2009 ◽  
pp. 1-17 ◽  
Author(s):  
K. Anamika ◽  
K. R. Abhinandan ◽  
K. Deshmukh ◽  
N. Srinivasan
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Protein Interaction ◽  
Transmembrane Domain ◽  
Homo Sapiens ◽  
Interaction Domain ◽  
Protein Protein Interaction ◽  
Domain 3 ◽  
Eukaryotic Organisms ◽  
And Function

Protein Kinase-Like Non-kinases (PKLNKs), which are closely related to protein kinases, lack the crucial catalytic aspartate in the catalytic loop, and hence cannot function as protein kinase, have been analysed. Using various sensitive sequence analysis methods, we have recognized 82 PKLNKs from four higher eukaryotic organisms, namely,Homo sapiens,Mus musculus,Rattus norvegicus, andDrosophila melanogaster. On the basis of their domain combination and function, PKLNKs have been classified mainly into four categories: (1) Ligand binding PKLNKs, (2) PKLNKs with extracellular protein-protein interaction domain, (3) PKLNKs involved in dimerization, and (4) PKLNKs with cytoplasmic protein-protein interaction module. While members of the first two classes of PKLNKs have transmembrane domain tethered to the PKLNK domain, members of the other two classes of PKLNKs are cytoplasmic in nature. The current classification scheme hopes to provide a convenient framework to classify the PKLNKs from other eukaryotes which would be helpful in deciphering their roles in cellular processes.

scholarly journals Estrogen-related receptor alpha directly binds to p53 and cooperatively controls colon cancer growth through the regulation of mitochondrial biogenesis and function

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Humberto De Vitto ◽  
Joohyun Ryu ◽  
Ali Calderon-Aparicio ◽  
Josh Monts ◽  
Raja Dey ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Protein Interaction ◽  
Mitochondrial Biogenesis ◽  
P53 Protein ◽  
Selection Criterion ◽  
In Vivo Studies ◽  
Clear Understanding ◽  
Protein Protein Interaction ◽  
Mutational Status ◽  
And Function

Abstract Background Of the genes that control mitochondrial biogenesis and function, ERRα emerges as a druggable metabolic target to be exploited for cancer therapy. Of the genes mutated in cancer, TP53 remains the most elusive to target. A clear understanding of how mitochondrial druggable targets can be accessed to exploit the underlying mechanism(s) explaining how p53-deficient tumors promote cell survival remains elusive. Methods We performed protein-protein interaction studies to demonstrate that ERRα binds to p53. Moreover, we used gene silencing and pharmacological approaches in tandem with quantitative proteomics analysis by SWATH-MS to investigate the role of the ERRα/p53 complex in mitochondrial biogenesis and function in colon cancer. Finally, we designed in vitro and in vivo studies to investigate the possibility of targeting colon cancers that exhibit defects in p53. Results Here, we are the first to identify a direct protein-protein interaction between the ligand-binding domain (LBD) of ERRα and the C-terminal domain (CTD) of p53. ERRα binds to p53 regardless of p53 mutational status. Furthermore, we show that the ERRα and p53 complex cooperatively control mitochondrial biogenesis and function. Targeting ERRα creates mitochondrial metabolic stresses, such as production of reactive oxygen species (ROS) and mitochondrial membrane permeabilization (MMP), leading to a greater cytotoxic effect that is dependent on the presence of p53. Pharmacological inhibition of ERRα impairs the growth of p53-deficient cells and of p53 mutant patient-derived colon xenografts (PDX). Conclusions Therefore, our data suggest that by using the status of the p53 protein as a selection criterion, the ERRα/p53 transcriptional axis can be exploited as a metabolic vulnerability.

scholarly journals Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional Complex

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 6001
Author(s):  
Ajaybabu V. Pobbati ◽  
Brian P. Rubin
Keyword(s):  
Transcription Factors ◽  
Small Molecules ◽  
Protein Interaction ◽  
Hydrophobic Residues ◽  
Common Features ◽  
Protein Protein Interaction ◽  
Pharmacokinetic Properties ◽  
Hydrophobic Portion ◽  
Transcriptional Complex ◽  
And Function

The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The transcriptional co-regulator YAP (its homolog TAZ) interact with the surface pockets of TEADs. Peptidomimetic modalities like cystine-dense peptides and YAP cyclic and linear peptides exploit surface pockets (interface 2 and interface 3) on TEADs and function as PPIDs. The TEAD surface might pose a challenge for generating an effective small molecule PPID. Interestingly, TEADs also have a central pocket that is distinct from the surface pockets, and which small molecules leverage exclusively to disrupt the YAP/TAZ-TEAD interaction (allosteric PPIDs). Although small molecules that occupy the central pocket belong to diverse classes, they display certain common features. They are flexible, which allows them to adopt a palmitate-like conformation, and they have a predominant hydrophobic portion that contacts several hydrophobic residues and a small hydrophilic portion that faces the central pocket opening. Despite such progress, more selective PPIDs that also display favorable pharmacokinetic properties and show tolerable toxicity profiles are required to evaluate the feasibility of using these PPIDs for cancer therapy.

scholarly journals Peptide aptamers define distinct EB1- and EB3-binding motifs and interfere with microtubule dynamics

2014 ◽  
Vol 25 (7) ◽  
pp. 1025-1036 ◽  
Author(s):  
Karolina Leśniewska ◽  
Emma Warbrick ◽  
Hiroyuki Ohkura
Keyword(s):  
Protein Interaction ◽  
Microtubule Dynamics ◽  
Interacting Proteins ◽  
Small Peptide ◽  
Peptide Aptamers ◽  
Binding Motifs ◽  
Powerful Technique ◽  
And Function ◽  
Sequence Requirements ◽  
In Cells

EB1 is a conserved protein that plays a central role in regulating microtubule dynamics and organization. It binds directly to microtubule plus ends and recruits other plus end–localizing proteins. Most EB1-binding proteins contain a Ser–any residue–Ile-Pro (SxIP) motif. Here we describe the isolation of peptide aptamers with optimized versions of this motif by screening for interaction with the Drosophila EB1 protein. The use of small peptide aptamers to competitively inhibit protein interaction and function is becoming increasingly recognized as a powerful technique. We show that SxIP aptamers can bind microtubule plus ends in cells and functionally act to displace interacting proteins by competitive binding. Their expression in developing flies can interfere with microtubules, altering their dynamics. We also identify aptamers binding to human EB1 and EB3, which have sequence requirements similar to but distinct from each other and from Drosophila EB1. This suggests that EB1 paralogues within one species may interact with overlapping but distinct sets of proteins in cells.

iPEP: peptides designed and selected for interfering with protein interaction and function

2008 ◽  
Vol 36 (6) ◽  
pp. 1442-1447 ◽  
Author(s):  
Jody M. Mason ◽  
Kristian M. Müller ◽  
Katja M. Arndt
Keyword(s):  
Protein Interaction ◽  
Electrostatic Interactions ◽  
Rational Design ◽  
Protein Fragment ◽  
Hydrophobic Collapse ◽  
Helix Formation ◽  
Protein Fragment Complementation ◽  
Folding Pathways ◽  
Library Screen ◽  
And Function

Semi-rational design is combined with PCAs (protein-fragment complementation assays) and phage-display screening techniques to generate a range of iPEPs (interfering peptides) that target therapeutically relevant proteins with much higher interaction stability than their native complexes. PCA selection has been improved to impose a competitive and negative design initiative on the library screen, thus simultaneously improving the specificity of assay ‘winners’. The folding pathways of designed pairs imply that early events are dominated by hydrophobic collapse and helix formation, whereas later events account for the consolidation of more intricate intermolecular electrostatic interactions.

scholarly journals Bacterial protein interaction networks: connectivity is ruled by gene conservation, essentiality and function

2021 ◽  
Vol 22 ◽  
Author(s):  
Maddalena Dilucca ◽  
Giulio Cimini ◽  
Andrea Giansanti
Keyword(s):  
Protein Interaction ◽  
Gene Conservation ◽  
Bacterial Protein ◽  
Bacterial Genomes ◽  
Orthologous Genes ◽  
Protein Protein Interaction ◽  
Functional Relationships ◽  
Ppi Networks ◽  
Evolutionary Trajectories ◽  
And Function

Background: Protein-protein interaction (PPI) networks are the backbone of all processes in living cells. In this work we relate conservation, essentiality and functional repertoire of a gene to the connectivity k (i.e. the number of interactions, links) of the corresponding protein in the PPI network. Methods: On a set of 42 bacterial genomes of different sizes, and with reasonably separated evolutionary trajectories, we investigate three issues: i) whether the distribution of connectivities changes between PPI subnetworks of essential and nonessential genes; ii) how gene conservation, measured both by the evolutionary retention index (ERI) and by evolutionary pressures, is related to the connectivity of the corresponding protein; iii) how PPI connectivities are modulated by evolutionary and functional relationships, as represented by the Clusters of Orthologous Genes (COGs). Results: We show that conservation, essentiality and functional specialisation of genes constrains the connectivity of the corresponding proteins in bacterial PPI networks. In particular, we isolated a core of highly connected proteins (connectivities k≥40), which is ubiquitous among the species considered here, though mostly visible in the degree distributions of bacteria with small genomes (less than 1000 genes). Conclusion: The genes that support this highly connected core are conserved, essential and, in most cases, belong to the COG cluster J, related to ribosomal functions and to the processing of genetic information.

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