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The present and the future of motif-mediated protein-protein interactions.

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The present and the future of motif-mediated protein-protein interactions.

Curr Opin Struct Biol. 2018 May 03;50:162-170

Authors: Seo MH, Kim PM

Abstract
Protein-protein interactions (PPIs) are essential to governing virtually all cellular processes. Of particular importance are the versatile motif-mediated interactions (MMIs), which are thus far underrepresented in available interaction data. This is largely due to technical difficulties inherent in the properties of MMIs, but due to the increasing recognition of the vital roles of MMIs in biology, several systematic approaches have recently been developed to detect novel MMIs. Consequently, rapidly growing numbers of motifs are being identified and pursued further for therapeutic applications. In this review, we discuss the current understanding on the diverse functions and disease-relevance of MMIs, the key methodologies for detection of MMIs, and the potential of MMIs for drug development.

PMID: 29730529 [PubMed - as supplied by publisher]



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Calcium influx differentially regulates migration velocity and directedness in response to electric field application.

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Calcium influx differentially regulates migration velocity and directedness in response to electric field application.

Exp Cell Res. 2018 May 02;:

Authors: Babona-Pilipos R, Liu N, Pritchard-Oh A, Mok A, Badawi D, Popovic MR, Morshead CM

Abstract
Neural precursor cells (NPCs) respond to externally applied direct current electrical fields (DCEFs) by undergoing rapid and directed migration toward the cathode in a process known as galvanotaxis. It is unknown if the underlying mechanisms of galvanotactic migration is common to non-electrosensitive cells and if so, how NPCs and other galvanotactic cells sense and transduce electrical fields into cellular motility. In this study, we show that distinct aspects of NPC galvanotactic migration: motility (quantified through |velocity|) and directedness, are differentially regulated by calcium. We use low-Ca2+ culture conditions; an intracellular Ca2+ chelator; and voltage gated calcium channel (VGCC) inhibitors to specific channels expressed on NPCs, to demonstrate the role of Ca2+ influx in DCEF-induced NPC migration. Consistent with existing literature, we show Ca2+ is involved in F-actin polymerization that lengthens NPC membrane protrusions necessary for cellular motility. However, inhibiting Ca2+ results in reduced velocity but has no effect on DCEF-induced directedness. This dissociation between velocity and directedness reveal that these migration parameters can be independently regulated, thus suggesting a parallel process of sensing DCEFs by NPCs.

PMID: 29729231 [PubMed - as supplied by publisher]



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Global analysis of genetic circuitry and adaptive mechanisms enabling resistance to the azole antifungal drugs.

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Global analysis of genetic circuitry and adaptive mechanisms enabling resistance to the azole antifungal drugs.

PLoS Genet. 2018 04;14(4):e1007319

Authors: Mount HO, Revie NM, Todd RT, Anstett K, Collins C, Costanzo M, Boone C, Robbins N, Selmecki A, Cowen LE

Abstract
Invasive fungal infections caused by the pathogen Candida albicans have transitioned from a rare curiosity to a major cause of human mortality. This is in part due to the emergence of resistance to the limited number of antifungals available to treat fungal infections. Azoles function by targeting the biosynthesis of ergosterol, a key component of the fungal cell membrane. Loss-of-function mutations in the ergosterol biosynthetic gene ERG3 mitigate azole toxicity and enable resistance that depends upon fungal stress responses. Here, we performed a genome-wide synthetic genetic array screen in Saccharomyces cerevisiae to map ERG3 genetic interactors and uncover novel circuitry important for azole resistance. We identified nine genes that enabled erg3-mediated azole resistance in the model yeast and found that only two of these genes had a conserved impact on resistance in C. albicans. Further, we screened a C. albicans homozygous deletion mutant library and identified 13 genes for which deletion enhances azole susceptibility. Two of the genes, RGD1 and PEP8, were also important for azole resistance acquired by diverse mechanisms. We discovered that loss of function of retrograde transport protein Pep8 overwhelms the functional capacity of the stress response regulator calcineurin, thereby abrogating azole resistance. To identify the mechanism through which the GTPase activator protein Rgd1 enables azole resistance, we selected for mutations that restore resistance in strains lacking Rgd1. Whole genome sequencing uncovered parallel adaptive mechanisms involving amplification of both chromosome 7 and a large segment of chromosome 3. Overexpression of a transporter gene on the right portion of chromosome 3, NPR2, was sufficient to enable azole resistance in the absence of Rgd1. Thus, we establish a novel mechanism of adaptation to drug-induced stress, define genetic circuitry underpinning azole resistance, and illustrate divergence in resistance circuitry over evolutionary time.

PMID: 29702647 [PubMed - indexed for MEDLINE]



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A digital microfluidic system for serological immunoassays in remote settings.

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A digital microfluidic system for serological immunoassays in remote settings.

Sci Transl Med. 2018 Apr 25;10(438):

Authors: Ng AHC, Fobel R, Fobel C, Lamanna J, Rackus DG, Summers A, Dixon C, Dryden MDM, Lam C, Ho M, Mufti NS, Lee V, Asri MAM, Sykes EA, Chamberlain MD, Joseph R, Ope M, Scobie HM, Knipes A, Rota PA, Marano N, Chege PM, Njuguna M, Nzunza R, Kisangau N, Kiogora J, Karuingi M, Burton JW, Borus P, Lam E, Wheeler AR

Abstract
Serosurveys are useful for assessing population susceptibility to vaccine-preventable disease outbreaks. Although at-risk populations in remote areas could benefit from this type of information, they face several logistical barriers to implementation, such as lack of access to centralized laboratories, cold storage, and transport of samples. We describe a potential solution: a compact and portable, field-deployable, point-of-care system relying on digital microfluidics that can rapidly test a small volume of capillary blood for disease-specific antibodies. This system uses inexpensive, inkjet-printed digital microfluidic cartridges together with an integrated instrument to perform enzyme-linked immunosorbent assays (ELISAs). We performed a field validation of the system's analytical performance at Kakuma refugee camp, a remote setting in northwestern Kenya, where we tested children aged 9 to 59 months and caregivers for measles and rubella immunoglobulin G (IgG). The IgG assays were determined to have sensitivities of 86% [95% confidence interval (CI), 79 to 91% (measles)] and 81% [95% CI, 73 to 88% (rubella)] and specificities of 80% [95% CI, 49 to 94% (measles)] and 91% [95% CI, 76 to 97% (rubella)] (measles, n = 140; rubella, n = 135) compared with reference tests (measles IgG and rubella IgG ELISAs from Siemens Enzygnost) conducted in a centralized laboratory. These results demonstrate a potential role for this point-of-care system in global serological surveillance, particularly in remote areas with limited access to centralized laboratories.

PMID: 29695457 [PubMed - in process]



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

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

Biochem Cell Biol. 2018 Apr 25;:

Authors: Taipale M

Abstract
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.

PMID: 29693415 [PubMed - as supplied by publisher]



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The Evolutionary Landscape of Localized Prostate Cancers Drives Clinical Aggression.

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The Evolutionary Landscape of Localized Prostate Cancers Drives Clinical Aggression.

Cell. 2018 Apr 14;:

Authors: Espiritu SMG, Liu LY, Rubanova Y, Bhandari V, Holgersen EM, Szyca LM, Fox NS, Chua MLK, Yamaguchi TN, Heisler LE, Livingstone J, Wintersinger J, Yousif F, Lalonde E, Rouette A, Salcedo A, Houlahan KE, Li CH, Huang V, Fraser M, van der Kwast T, Morris QD, Bristow RG, Boutros PC

Abstract
The majority of newly diagnosed prostate cancers are slow growing, with a long natural life history. Yet a subset can metastasize with lethal consequences. We reconstructed the phylogenies of 293 localized prostate tumors linked to clinical outcome data. Multiple subclones were detected in 59% of patients, and specific subclonal architectures associate with adverse clinicopathological features. Early tumor development is characterized by point mutations and deletions followed by later subclonal amplifications and changes in trinucleotide mutational signatures. Specific genes are selectively mutated prior to or following subclonal diversification, including MTOR, NKX3-1, and RB1. Patients with low-risk monoclonal tumors rarely relapse after primary therapy (7%), while those with high-risk polyclonal tumors frequently do (61%). The presence of multiple subclones in an index biopsy may be necessary, but not sufficient, for relapse of localized prostate cancer, suggesting that evolution-aware biomarkers should be studied in prospective studies of low-risk tumors suitable for active surveillance.

PMID: 29681457 [PubMed - as supplied by publisher]



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Chemically controlled aggregation of pluripotent stem cells.

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Chemically controlled aggregation of pluripotent stem cells.

Biotechnol Bioeng. 2018 Apr 21;:

Authors: Lipsitz YY, Tonge P, Zandstra PW

Abstract
Heterogeneity in pluripotent stem cell (PSC) aggregation leads to variability in mass transfer and signaling gradients between aggregates, which results in heterogeneous differentiation and therefore variability in product quality and yield. We have characterized a chemical based method to control aggregate size within a specific, tunable range with low heterogeneity, thereby reducing process variability in PSC expansion. This method enables controlled, scalable, stirred suspension based manufacturing of PSC cultures which are critical for the translation of regenerative medicine strategies to clinical products. This article is protected by copyright. All rights reserved.

PMID: 29679475 [PubMed - as supplied by publisher]



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Donated chemical probes for open science.

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Donated chemical probes for open science.

Elife. 2018 Apr 20;7:

Authors: Müller S, Ackloo S, Arrowsmith CH, Bauser M, Baryza JL, Blagg J, Böttcher J, Bountra C, Brown PJ, Bunnage ME, Carter AJ, Damerell D, Dötsch V, Drewry DH, Edwards AM, Edwards J, Elkins JM, Fischer C, Frye SV, Gollner A, Grimshaw CE, IJzerman A, Hanke T, Hartung IV, Hitchcock S, Howe T, Hughes TV, Laufer S, Li VM, Liras S, Marsden BD, Matsui H, Mathias J, O'Hagan RC, Owen DR, Pande V, Rauh D, Rosenberg SH, Roth BL, Schneider NS, Scholten C, Singh Saikatendu K, Simeonov A, Takizawa M, Tse C, Thompson PR, Treiber DK, Viana AY, Wells CI, Willson TM, Zuercher WJ, Knapp S, Mueller-Fahrnow A

Abstract
Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (<ext-link ext-link-type="uri" xlink:href="https://openscienceprobes.sgc-frankfurt.de">https://openscienceprobes.sgc-frankfurt.de</ext-link><ext-link ext-link-type="uri" xlink:href="https://openscienceprobes.sgc-frankfurt.de/">/</ext-link>). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project.

PMID: 29676732 [PubMed - in process]



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Systematic analysis of complex genetic interactions.

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Systematic analysis of complex genetic interactions.

Science. 2018 04 20;360(6386):

Authors: Kuzmin E, VanderSluis B, Wang W, Tan G, Deshpande R, Chen Y, Usaj M, Balint A, Mattiazzi Usaj M, van Leeuwen J, Koch EN, Pons C, Dagilis AJ, Pryszlak M, Wang JZY, Hanchard J, Riggi M, Xu K, Heydari H, San Luis BJ, Shuteriqi E, Zhu H, Van Dyk N, Sharifpoor S, Costanzo M, Loewith R, Caudy A, Bolnick D, Brown GW, Andrews BJ, Boone C, Myers CL

Abstract
To systematically explore complex genetic interactions, we constructed ~200,000 yeast triple mutants and scored negative trigenic interactions. We selected double-mutant query genes across a broad spectrum of biological processes, spanning a range of quantitative features of the global digenic interaction network and tested for a genetic interaction with a third mutation. Trigenic interactions often occurred among functionally related genes, and essential genes were hubs on the trigenic network. Despite their functional enrichment, trigenic interactions tended to link genes in distant bioprocesses and displayed a weaker magnitude than digenic interactions. We estimate that the global trigenic interaction network is ~100 times as large as the global digenic network, highlighting the potential for complex genetic interactions to affect the biology of inheritance, including the genotype-to-phenotype relationship.

PMID: 29674565 [PubMed - indexed for MEDLINE]



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Systems analysis of the genetic interaction network of yeast molecular chaperones.

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Systems analysis of the genetic interaction network of yeast molecular chaperones.

Mol Omics. 2018 Apr 16;14(2):82-94

Authors: Rizzolo K, Kumar A, Kakihara Y, Phanse S, Minic Z, Snider J, Stagljar I, Zilles S, Babu M, Houry WA

Abstract
Molecular chaperones are typically promiscuous interacting proteins that function globally in the cell to maintain protein homeostasis. Recently, we had carried out experiments that elucidated a comprehensive interaction network for the core 67 chaperones and 15 cochaperones in the budding yeast Saccharomyces cerevisiae [Rizzolo et al., Cell Rep., 2017, 20, 2735-2748]. Here, the genetic (i.e. epistatic) interaction network obtained for chaperones was further analyzed, revealing that the global topological parameters of the resulting network have a more central role in mediating interactions in comparison to the rest of the proteins in the cell. Most notably, we observed Hsp10, Hsp70 Ssz1 chaperone, and Hsp90 cochaperone Cdc37 to be the main drivers of the network architecture. Systematic analysis on the physicochemical properties for all chaperone interactors further revealed the presence of preferential domains and folds that are highly interactive with chaperones such as the WD40 repeat domain. Further analysis with established cellular complexes revealed the involvement of R2TP chaperone in quaternary structure formation. Our results thus provide a global overview of the chaperone network properties in yeast, expanding our understanding of their functional diversity and their role in protein homeostasis.

PMID: 29659649 [PubMed]



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