scholarly journals Mutation Edgotype Drives Fitness Effect in Human

2021 ◽  
Vol 1 ◽  
Author(s):  
Mohamed Ghadie ◽  
Yu Xia
Keyword(s):  
Protein Interactions ◽  
Human Life ◽  
Three Dimensional ◽  
Purifying Selection ◽  
Missense Mutations ◽  
Wild Type ◽  
Fitness Effect ◽  
Protein Protein Interaction ◽  
Binding Interface ◽  
Pathogenic Mutations

Missense mutations are known to perturb protein-protein interaction networks (known as interactome networks) in different ways. However, it remains unknown how different interactome perturbation patterns (“edgotypes”) impact organismal fitness. Here, we estimate the fitness effect of missense mutations with different interactome perturbation patterns in human, by calculating the fractions of neutral and deleterious mutations that do not disrupt PPIs (“quasi-wild-type”), or disrupt PPIs either by disrupting the binding interface (“edgetic”) or by disrupting overall protein stability (“quasi-null”). We first map pathogenic mutations and common non-pathogenic mutations onto homology-based three-dimensional structural models of proteins and protein-protein interactions in human. Next, we perform structure-based calculations to classify each mutation as either quasi-wild-type, edgetic, or quasi-null. Using our predicted as well as experimentally determined interactome perturbation patterns, we estimate that >∼40% of quasi-wild-type mutations are effectively neutral and the remaining are mostly mildly deleterious, that >∼75% of edgetic mutations are only mildly deleterious, and that up to ∼75% of quasi-null mutations may be strongly detrimental. These estimates are the first such estimates of fitness effect for different network perturbation patterns in any interactome. Our results suggest that while mutations that do not disrupt the interactome tend to be effectively neutral, the majority of human PPIs are under strong purifying selection and the stability of most human proteins is essential to human life.

Extracting Biological Significant Subnetworks from Protein-Protein Interactions Induced by Differentially Expressed Genes of HIV-1 Vpr Variants

2015 ◽  
Vol 4 (4) ◽  
pp. 35-51 ◽  
Author(s):  
Bandana Barman ◽  
Anirban Mukhopadhyay
Keyword(s):  
Differentially Expressed Genes ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Protein Interaction Network ◽  
Interaction Network ◽  
Differentially Expressed ◽  
Wild Type ◽  
Protein Protein Interaction ◽  
Ppi Networks ◽  
Hiv 1

Identification of protein interaction network is very important to find the cell signaling pathway for a particular disease. The authors have found the differentially expressed genes between two sample groups of HIV-1. Samples are wild type HIV-1 Vpr and HIV-1 mutant Vpr. They did statistical t-test and found false discovery rate (FDR) to identify the genes increased in expression (up-regulated) or decreased in expression (down-regulated). In the test, the authors have computed q-values of test to identify minimum FDR which occurs. As a result they found 172 differentially expressed genes between their sample wild type HIV-1 Vpr and HIV-1 mutant Vpr, R80A. They found 68 up-regulated genes and 104 down-regulated genes. From the 172 differentially expressed genes the authors found protein-protein interaction network with string-db and then clustered (subnetworks) the PPI networks with cytoscape3.0. Lastly, the authors studied significance of subnetworks with performing gene ontology and also studied the KEGG pathway of those subnetworks.

scholarly journals ATXN1 N-terminal region explains the binding differences of wild-type and expanded forms

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Sara Rocha ◽  
Jorge Vieira ◽  
Noé Vázquez ◽  
Hugo López-Fernández ◽  
Florentino Fdez-Riverola ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Structures ◽  
Interaction Strength ◽  
Terminal Region ◽  
Spinocerebellar Ataxia Type ◽  
Wild Type ◽  
Binding Interface ◽  
Strength Of Interaction ◽  
The Difference ◽  
Polyq Expansion

Abstract Background Wild-type (wt) polyglutamine (polyQ) regions are implicated in stabilization of protein-protein interactions (PPI). Pathological polyQ expansion, such as that in human Ataxin-1 (ATXN1), that causes spinocerebellar ataxia type 1 (SCA1), results in abnormal PPI. For ATXN1 a larger number of interactors has been reported for the expanded (82Q) than the wt (29Q) protein. Methods To understand how the expanded polyQ affects PPI, protein structures were predicted for wt and expanded ATXN1, as well as, for 71 ATXN1 interactors. Then, the binding surfaces of wt and expanded ATXN1 with the reported interactors were inferred. Results Our data supports that the polyQ expansion alters the ATXN1 conformation and that it enhances the strength of interaction with ATXN1 partners. For both ATXN1 variants, the number of residues at the predicted binding interface are greater after the polyQ, mainly due to the AXH domain. Moreover, the difference in the interaction strength of the ATXN1 variants was due to an increase in the number of interactions at the N-terminal region, before the polyQ, for the expanded form. Conclusions There are three regions at the AXH domain that are essential for ATXN1 PPI. The N-terminal region is responsible for the strength of the PPI with the ATXN1 variants. How the predicted motifs in this region affect PPI is discussed, in the context of ATXN1 post-transcriptional modifications.

scholarly journals Proximal Protein Interaction Landscape of RAS Paralogs

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3326 ◽  
Author(s):  
Benoît Béganton ◽  
Etienne Coyaud ◽  
Estelle M. N. Laurent ◽  
Alain Mangé ◽  
Julien Jacquemetton ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Protein Interactions ◽  
Biological Activities ◽  
Mammalian Species ◽  
Variable Region ◽  
Specific Protein ◽  
Protein Networks ◽  
Ras Proteins ◽  
Wild Type ◽  
Protein Protein Interaction

RAS proteins (KRAS, NRAS and HRAS) are frequently activated in different cancer types (e.g., non-small cell lung cancer, colorectal cancer, melanoma and bladder cancer). For many years, their activities were considered redundant due to their high degree of sequence homology (80% identity) and their shared upstream and downstream protein partners. However, the high conservation of the Hyper-Variable-Region across mammalian species, the preferential activation of different RAS proteins in specific tumor types and the specific post-translational modifications and plasma membrane-localization of each paralog suggest they could ensure discrete functions. To gain insights into RAS proteins specificities, we explored their proximal protein–protein interaction landscapes using the proximity-dependent biotin identification technology (BioID) in Flp-In T-REx 293 cell lines stably transfected and inducibly expressing wild type KRAS4B, NRAS or HRAS. We identified more than 800 high-confidence proximal interactors, allowing us to propose an unprecedented comparative analysis of wild type RAS paralogs protein networks. These data bring novel information on poorly characterized RAS functions, e.g., its putative involvement in metabolic pathways, and on shared as well as paralog-specific protein networks that could partially explain the complexity of RAS functions. These networks of protein interactions open numerous avenues to better understand RAS paralogs biological activities.

scholarly journals mCSM-PPI2: predicting the effects of mutations on protein–protein interactions

2019 ◽  
Vol 47 (W1) ◽  
pp. W338-W344 ◽  
Author(s):  
Carlos H M Rodrigues ◽  
Yoochan Myung ◽  
Douglas E V Pires ◽  
David B Ascher
Keyword(s):  
Protein Interactions ◽  
Interaction Network ◽  
Evolutionary Information ◽  
Biological Processes ◽  
Missense Mutations ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Residue Interaction ◽  
User Friendly ◽  
Network Metrics

AbstractProtein–protein Interactions are involved in most fundamental biological processes, with disease causing mutations enriched at their interfaces. Here we present mCSM-PPI2, a novel machine learning computational tool designed to more accurately predict the effects of missense mutations on protein–protein interaction binding affinity. mCSM-PPI2 uses graph-based structural signatures to model effects of variations on the inter-residue interaction network, evolutionary information, complex network metrics and energetic terms to generate an optimised predictor. We demonstrate that our method outperforms previous methods, ranking first among 26 others on CAPRI blind tests. mCSM-PPI2 is freely available as a user friendly webserver at http://biosig.unimelb.edu.au/mcsm_ppi2/.

scholarly journals A Mutation in γ-Tubulin Alters Microtubule Dynamics and Organization and Is Synthetically Lethal with the Kinesin-like Protein Pkl1p

2000 ◽  
Vol 11 (4) ◽  
pp. 1225-1239 ◽  
Author(s):  
Janet L. Paluh ◽  
Eva Nogales ◽  
Berl R. Oakley ◽  
Kent McDonald ◽  
Alison L. Pidoux ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Three Dimensional ◽  
Time Lapse ◽  
Spindle Pole ◽  
Microtubule Dynamics ◽  
Wild Type ◽  
Protein Protein Interactions ◽  
Cytoplasmic Microtubule ◽  
Spindle Poles ◽  
Tubulin Protein

Mitotic segregation of chromosomes requires spindle pole functions for microtubule nucleation, minus end organization, and regulation of dynamics. γ-Tubulin is essential for nucleation, and we now extend its role to these latter processes. We have characterized a mutation in γ-tubulin that results in cold-sensitive mitotic arrest with an elongated bipolar spindle but impaired anaphase A. At 30°C cytoplasmic microtubule arrays are abnormal and bundle into single larger arrays. Three-dimensional time-lapse video microscopy reveals that microtubule dynamics are altered. Localization of the mutant γ-tubulin is like the wild-type protein. Prediction of γ-tubulin structure indicates that non-α/β-tubulin protein–protein interactions could be affected. The kinesin-like protein (klp)Pkl1p localizes to the spindle poles and spindle and is essential for viability of the γ-tubulin mutant and in multicopy for normal cell morphology at 30°C. Localization and function of Pkl1p in the mutant appear unaltered, consistent with a redundant function for this protein in wild type. Our data indicate a broader role for γ-tubulin at spindle poles in regulating aspects of microtubule dynamics and organization. We propose that Pkl1p rescues an impaired function of γ-tubulin that involves non-tubulin protein–protein interactions, presumably with a second motor, MAP, or MTOC component.

scholarly journals Interactions of Human hMSH2 with hMSH3 and hMSH2 with hMSH6: Examination of Mutations Found in Hereditary Nonpolyposis Colorectal Cancer

1998 ◽  
Vol 18 (11) ◽  
pp. 6616-6623 ◽  
Author(s):  
Shawn Guerrette ◽  
Teresa Wilson ◽  
Scott Gradia ◽  
Richard Fishel
Keyword(s):  
Colorectal Cancer ◽  
Protein Interactions ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Missense Mutations ◽  
Protein Protein Interaction ◽  
Static Interaction ◽  
Repair Protein ◽  
Hereditary Nonpolyposis ◽  
Interaction Regions ◽  
Mismatch Repair Protein

ABSTRACT Mutations in the human mismatch repair protein hMSH2 have been found to cosegregate with hereditary nonpolyposis colorectal cancer (HNPCC). Previous biochemical and physical studies have shown that hMSH2 forms specific mispair binding complexes with hMSH3 and hMSH6. We have further characterized these protein interactions by mapping the contact regions within the hMSH2-hMSH3 and the hMSH2-hMSH6 heterodimers. We demonstrate that there are at least two distinct interaction regions of hMSH2 with hMSH3 and hMSH2 with hMSH6. Interestingly, the interaction regions of hMSH2 with either hMSH3 or hMSH6 are identical and there is a coordinated linear orientation of these regions. We examined several missense alterations of hMSH2 found in HNPCC kindreds that are contained within the consensus interaction regions. None of these missense mutations displayed a defect in protein-protein interaction. These data support the notion that these HNPCC-associated mutations may affect some other function of the heterodimeric complexes than simply the static interaction of hMSH2 with hMSH3 or hMSH2 with hMSH6.

A structural network associated with the kallikrein-kinin and renin-angiotensin systems

2010 ◽  
Vol 391 (4) ◽  
Author(s):  
Veronika Stoka ◽  
Vito Turk
Keyword(s):  
Protein Interactions ◽  
Three Dimensional ◽  
Type I ◽  
Protein Protein Interactions ◽  
Renin Angiotensin ◽  
Protein Protein Interaction ◽  
Protein Interfaces ◽  
Structural Network ◽  
Domain Interactions ◽  
Fibronectin Type

Abstract The kallikrein-kinin and renin-angiotensin (KKS-RAS) systems represent two highly regulated proteolytic systems that are involved in several physiological and pathological processes. Although their protein-protein interactions can be studied using experimental approaches, it is difficult to differentiate between direct physical interactions and functional associations, which do not involve direct atomic contacts between macromolecules. This information can be obtained from an atomic-resolution characterization of the protein interfaces. As a result of this, various three-dimensional-based protein-protein interaction databases have become available. To gain insight into the multilayered interaction of the KKS-RAS systems, we present a protein network that is built up on three-dimensional domain-domain interactions. The essential domains that link these systems are as follows: Cystatin, Peptidase_C1, Thyroglobulin_1, Insulin, CIMR (Cation-independent mannose-6-phosphate receptor repeat), fn2 (Fibronectin type II domain), fn1 (Fibronectin type I domain), EGF, Trypsin, and Serpin. We found that the CIMR domain is located at the core of the network, thus connecting both systems. From the latter, all domain interactors up to level 4 were retrieved, thus displaying a more comprehensive representation of the KKS-RAS structural network.

scholarly journals Prediction of Protein–Protein Interaction Sites Based on Stratified Attentional Mechanisms

2021 ◽  
Vol 12 ◽  
Author(s):  
Minli Tang ◽  
Longxin Wu ◽  
Xinyu Yu ◽  
Zhaoqi Chu ◽  
Shuting Jin ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Protein Interactions ◽  
Human Life ◽  
Amino Acid Position ◽  
Biological Macromolecules ◽  
Protein Protein Interaction ◽  
Interaction Sites ◽  
Scoring Matrix ◽  
Protein Interaction Sites ◽  
Better Than

Proteins are the basic substances that undertake human life activities, and they often perform their biological functions through interactions with other biological macromolecules, such as cell transmission and signal transduction. Predicting the interaction sites between proteins can deepen the understanding of the principle of protein interactions, but traditional experimental methods are time-consuming and labor-intensive. In this study, a new hierarchical attention network structure, named HANPPIS, by adding six effective features of protein sequence, position-specific scoring matrix (PSSM), secondary structure, pre-training vector, hydrophilic, and amino acid position, is proposed to predict protein–protein interaction (PPI) sites. The experiment proved that our model has obtained very effective results, which was better than the existing advanced calculation methods. More importantly, we used the double-layer attention mechanism to improve the interpretability of the model and to a certain extent solved the problem of the “black box” of deep neural networks, which can be used as a reference for location positioning on the biological level.

scholarly journals The plasma membrane as a competitive inhibitor and positive allosteric modulator of KRas4B signaling

2019 ◽  
Author(s):  
C. Neale ◽  
A.E. García
Keyword(s):  
Protein Interactions ◽  
Membrane Surface ◽  
Three Dimensional ◽  
Competitive Inhibitor ◽  
Effector Proteins ◽  
Globular Domain ◽  
Ras Proteins ◽  
Oncogenic Signaling ◽  
Binding Interface ◽  
Effector Binding

AbstractMutant Ras proteins are important drivers of human cancers, yet no approved drugs act directly on this difficult target. Over the last decade, the idea has emerged that oncogenic signaling can be diminished by molecules that drive Ras into orientations in which effector binding interfaces are occluded by the cell membrane. To support this approach to drug discovery, we characterize the orientational preferences of membrane-bound K-Ras4B in 1.45 milliseconds aggregate time of atomistic molecular dynamics simulations. Individual simulations probe active or inactive states of Ras on membranes with or without anionic lipids. We find that the membrane orientation of Ras is relatively insensitive to its bound guanine nucleotide and activation state but depends strongly on interactions with anionic phosphatidylserine lipids. These lipids slow Ras’ translational and orientational diffusion and promote a discrete population in which small changes in orientation control Ras’ competence to bind multiple regulator and effector proteins. Our results suggest that compound-directed conversion of constitutively active mutant Ras into functionally inactive forms may be accessible via subtle perturbations of Ras’ orientational preferences at the membrane surface.Statement of SignificanceMutations that lock Ras proteins in active states can undermine cellular decision making and drive cancer. Because there are no drugs to deactivate Ras, we use simulations to relate Ras’ three-dimensional orientation at the membrane surface to its signaling competence. Data shows that Ras reorientation is generally rapid, but can be trapped in one of three states by membrane adhesion of the globular signaling domain. One of these states is stabilized by negatively charged lipids and brings an effector binding interface toward the membrane surface, potentially obstructing protein-protein interactions required for propagation of the growth signal. Rare events drive a second type of membrane-based signaling obstruction that correlate with configurational changes in Ras’ globular domain, yielding a potential drug target.

scholarly journals Selective functional inhibition of a tumor-derived p53 mutant by cytosolic chaperones identified using split-YFP in budding yeast

2021 ◽  
Author(s):  
Ashley S. Denney ◽  
Andrew D. Weems ◽  
Michael A. McMurray
Keyword(s):  
Three Dimensional ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Temperature Sensitive ◽  
Missense Mutations ◽  
Tumor Suppressor P53 ◽  
Wild Type ◽  
Type Function ◽  
Negative Effect ◽  
Chaperone Interactions

ABSTRACTLife requires the oligomerization of individual proteins into higher-order assemblies. In order to form functional oligomers, monomers must adopt appropriate three-dimensional structures. Molecular chaperones transiently bind nascent or misfolded proteins to promote proper folding. Single missense mutations frequently cause disease by perturbing folding despite chaperone engagement. A misfolded mutant capable of oligomerizing with wild-type proteins can dominantly poison oligomer function. We previously found evidence that human-disease-linked mutations in Saccharomyces cerevisiae septin proteins slow folding and attract chaperones, resulting in a kinetic delay in oligomerization that prevents the mutant from interfering with wild-type function. Here we build upon our septin studies to develop a new approach to identifying chaperone interactions in living cells, and use it to expand our understanding of chaperone involvement, kinetic folding delays, and oligomerization in the recessive behavior of tumor-derived mutants of the tumor suppressor p53. We find evidence of increased binding of several cytosolic chaperones to a recessive, misfolding-prone mutant, p53(V272M). Similar to our septin results, chaperone overexpression inhibits the function of p53(V272M) with minimal effect on the wild type. Unlike mutant septins, p53(V272M) is not kinetically delayed under conditions in which it is functional. Instead, it interacts with wild-type p53 but this interaction is temperature sensitive. At high temperatures or upon chaperone overexpression, p53(V272M) is excluded from the nucleus and cannot function or perturb wild-type function. Chaperone inhibition liberates the mutant to enter the nucleus where it has a slight dominant-negative effect. These findings provide new insights into the effects of missense mutations.

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