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Yeast Aim21/Tda2 both regulates free actin by reducing barbed end assembly and forms a complex with Cap1/Cap2 to balance actin assembly between patches and cables.

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Yeast Aim21/Tda2 both regulates free actin by reducing barbed end assembly and forms a complex with Cap1/Cap2 to balance actin assembly between patches and cables.

Mol Biol Cell. 2018 Feb 21;:

Authors: Shin M, van Leeuwen J, Boone C, Bretscher A

Abstract
How cells balance the incorporation of actin into diverse structures is poorly understood. In budding yeast, a single actin monomer pool is used to build both actin cables involved in polarized growth and actin cortical patches involved in endocytosis. Here we report how Aim21/Tda2 is recruited to the cortical region of actin patches, where it negatively regulates actin assembly to elevate the available actin monomer pool. Aim21 has four polyproline regions and is recruited by two SH3-containing patch proteins Bbc1 and Abp1. The C-terminal region, which is required for its function, binds Tda2. Cell biological and biochemical data reveal that Aim21/Tda2 is a negative regulator of barbed end F-actin assembly, and this activity is necessary for efficient endocytosis and plays a pivotal role in balancing the distribution of actin between cables and patches. Aim21/Tda2 also forms a complex with the F-actin barbed end capping protein Cap1/Cap2, revealing an interplay between regulators, and showing the complexity of regulation of barbed end assembly.

PMID: 29467252 [PubMed - as supplied by publisher]



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Photo-immobilized EGF chemical gradients differentially impact breast cancer cell invasion and drug response in defined 3D hydrogels.

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Photo-immobilized EGF chemical gradients differentially impact breast cancer cell invasion and drug response in defined 3D hydrogels.

Biomaterials. 2018 Feb 13;:

Authors: Fisher SA, Tam RY, Fokina A, Mahmoodi MM, Distefano MD, Shoichet MS

Abstract
Breast cancer cell invasion is influenced by growth factor concentration gradients in the tumor microenvironment. However, studying the influence of growth factor gradients on breast cancer cell invasion is challenging due to both the complexities of in vivo models and the difficulties in recapitulating the tumor microenvironment with defined gradients using in vitro models. A defined hyaluronic acid (HA)-based hydrogel crosslinked with matrix metalloproteinase (MMP) cleavable peptides and modified with multiphoton labile nitrodibenzofuran (NDBF) was synthesized to photochemically immobilize epidermal growth factor (EGF) gradients. We demonstrate that EGF gradients can differentially influence breast cancer cell invasion and drug response in cell lines with different EGF receptor (EGFR) expression levels. Photopatterned EGF gradients increase the invasion of moderate EGFR expressing MDA-MB-231 cells, reduce invasion of high EGFR expressing MDA-MB-468 cells, and have no effect on invasion of low EGFR-expressing MCF-7 cells. We evaluate MDA-MB-231 and MDA-MB-468 cell response to the clinically tested EGFR inhibitor, cetuximab. Interestingly, the cellular response to cetuximab is completely different on the EGF gradient hydrogels: cetuximab decreases MDA-MB-231 cell invasion but increases MDA-MB-468 cell invasion and cell number, thus demonstrating the importance of including cell-microenvironment interactions when evaluating drug targets.

PMID: 29452913 [PubMed - as supplied by publisher]



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The Human Transcription Factors.

The Human Transcription Factors.

Cell. 2018 Feb 08;172(4):650-665

Authors: Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, Chen X, Taipale J, Hughes TR, Weirauch MT

Abstract
Transcription factors (TFs) recognize specific DNA sequences to control chromatin and transcription, forming a complex system that guides expression of the genome. Despite keen interest in understanding how TFs control gene expression, it remains challenging to determine how the precise genomic binding sites of TFs are specified and how TF binding ultimately relates to regulation of transcription. This review considers how TFs are identified and functionally characterized, principally through the lens of a catalog of over 1,600 likely human TFs and binding motifs for two-thirds of them. Major classes of human TFs differ markedly in their evolutionary trajectories and expression patterns, underscoring distinct functions. TFs likewise underlie many different aspects of human physiology, disease, and variation, highlighting the importance of continued effort to understand TF-mediated gene regulation.

PMID: 29425488 [PubMed - in process]



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Recent Progress in CFTR Interactome Mapping and Its Importance for Cystic Fibrosis.

Recent Progress in CFTR Interactome Mapping and Its Importance for Cystic Fibrosis.

Front Pharmacol. 2017;8:997

Authors: Lim SH, Legere EA, Snider J, Stagljar I

Abstract
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a chloride channel found in secretory epithelia with a plethora of known interacting proteins. Mutations in the CFTR gene cause cystic fibrosis (CF), a disease that leads to progressive respiratory illness and other complications of phenotypic variance resulting from perturbations of this protein interaction network. Studying the collection of CFTR interacting proteins and the differences between the interactomes of mutant and wild type CFTR provides insight into the molecular machinery of the disease and highlights possible therapeutic targets. This mini review focuses on functional genomics and proteomics approaches used for systematic, high-throughput identification of CFTR-interacting proteins to provide comprehensive insight into CFTR regulation and function.

PMID: 29403380 [PubMed]



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High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies.

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High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies.

Mol Cell. 2018 Feb 01;69(3):517-532.e11

Authors: Youn JY, Dunham WH, Hong SJ, Knight JDR, Bashkurov M, Chen GI, Bagci H, Rathod B, MacLeod G, Eng SWM, Angers S, Morris Q, Fabian M, Côté JF, Gingras AC

Abstract
mRNA processing, transport, translation, and ultimately degradation involve a series of dedicated protein complexes that often assemble into large membraneless structures such as stress granules (SGs) and processing bodies (PBs). Here, systematic in vivo proximity-dependent biotinylation (BioID) analysis of 119 human proteins associated with different aspects of mRNA biology uncovers 7424 unique proximity interactions with 1,792 proteins. Classical bait-prey analysis reveals connections of hundreds of proteins to distinct mRNA-associated processes or complexes, including the splicing and transcriptional elongation machineries (protein phosphatase 4) and the CCR4-NOT deadenylase complex (CEP85, RNF219, and KIAA0355). Analysis of correlated patterns between endogenous preys uncovers the spatial organization of RNA regulatory structures and enables the definition of 144 core components of SGs and PBs. We report preexisting contacts between most core SG proteins under normal growth conditions and demonstrate that several core SG proteins (UBAP2L, CSDE1, and PRRC2C) are critical for the formation of microscopically visible SGs.

PMID: 29395067 [PubMed - in process]



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Method to generate highly stable D-amino acid analogs of bioactive helical peptides using a mirror image of the entire PDB.

Method to generate highly stable D-amino acid analogs of bioactive helical peptides using a mirror image of the entire PDB.

Proc Natl Acad Sci U S A. 2018 Jan 29;:

Authors: Garton M, Nim S, Stone TA, Wang KE, Deber CM, Kim PM

Abstract
Biologics are a rapidly growing class of therapeutics with many advantages over traditional small molecule drugs. A major obstacle to their development is that proteins and peptides are easily destroyed by proteases and, thus, typically have prohibitively short half-lives in human gut, plasma, and cells. One of the most effective ways to prevent degradation is to engineer analogs from dextrorotary (D)-amino acids, with up to 105-fold improvements in potency reported. We here propose a general peptide-engineering platform that overcomes limitations of previous methods. By creating a mirror image of every structure in the Protein Data Bank (PDB), we generate a database of ∼2.8 million D-peptides. To obtain a D-analog of a given peptide, we search the (D)-PDB for similar configurations of its critical-"hotspot"-residues. As a proof of concept, we apply our method to two peptides that are Food and Drug Administration approved as therapeutics for diabetes and osteoporosis, respectively. We obtain D-analogs that activate the GLP1 and PTH1 receptors with the same efficacy as their natural counterparts and show greatly increased half-life.

PMID: 29378946 [PubMed - as supplied by publisher]



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Modeling signaling-dependent pluripotency with Boolean logic to predict cell fate transitions.

Modeling signaling-dependent pluripotency with Boolean logic to predict cell fate transitions.

Mol Syst Biol. 2018 Jan 29;14(1):e7952

Authors: Yachie-Kinoshita A, Onishi K, Ostblom J, Langley MA, Posfai E, Rossant J, Zandstra PW

Abstract
Pluripotent stem cells (PSCs) exist in multiple stable states, each with specific cellular properties and molecular signatures. The mechanisms that maintain pluripotency, or that cause its destabilization to initiate development, are complex and incompletely understood. We have developed a model to predict stabilized PSC gene regulatory network (GRN) states in response to input signals. Our strategy used random asynchronous Boolean simulations (R-ABS) to simulate single-cell fate transitions and strongly connected components (SCCs) strategy to represent population heterogeneity. This framework was applied to a reverse-engineered and curated core GRN for mouse embryonic stem cells (mESCs) and used to simulate cellular responses to combinations of five signaling pathways. Our simulations predicted experimentally verified cell population compositions and input signal combinations controlling specific cell fate transitions. Extending the model to PSC differentiation, we predicted a combination of signaling activators and inhibitors that efficiently and robustly generated a Cdx2+Oct4- cells from naïve mESCs. Overall, this platform provides new strategies to simulate cell fate transitions and the heterogeneity that typically occurs during development and differentiation.

PMID: 29378814 [PubMed - in process]



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Unification of Protein Abundance Datasets Yields a Quantitative Saccharomyces cerevisiae Proteome.

Unification of Protein Abundance Datasets Yields a Quantitative Saccharomyces cerevisiae Proteome.

Cell Syst. 2018 Jan 17;:

Authors: Ho B, Baryshnikova A, Brown GW

Abstract
Protein activity is the ultimate arbiter of function in most cellular pathways, and protein concentration is fundamentally connected to protein action. While the proteome of yeast has been subjected to the most comprehensive analysis of any eukaryote, existing datasets are difficult to compare, and there is no consensus abundance value for each protein. We evaluated 21 quantitative analyses of the S. cerevisiae proteome, normalizing and converting all measurements of protein abundance into the intuitive measurement of absolute molecules per cell. We estimate the cellular abundance of 92% of the proteins in the yeast proteome and assess the variation in each abundance measurement. Using our protein abundance dataset, we find that a global response to diverse environmental stresses is not detected at the level of protein abundance, we find that protein tags have only a modest effect on protein abundance, and we identify proteins that are differentially regulated at the mRNA abundance, mRNA translation, and protein abundance levels.

PMID: 29361465 [PubMed - as supplied by publisher]



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The Chemical Fluctuation Theorem governing gene expression.

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The Chemical Fluctuation Theorem governing gene expression.

Nat Commun. 2018 Jan 19;9(1):297

Authors: Park SJ, Song S, Yang GS, Kim PM, Yoon S, Kim JH, Sung J

Abstract
Gene expression is a complex stochastic process composed of numerous enzymatic reactions with rates coupled to hidden cell-state variables. Despite advances in single-cell technologies, the lack of a theory accurately describing the gene expression process has restricted a robust, quantitative understanding of gene expression variability among cells. Here we present the Chemical Fluctuation Theorem (CFT), providing an accurate relationship between the environment-coupled chemical dynamics of gene expression and gene expression variability. Combined with a general, accurate model of environment-coupled transcription processes, the CFT provides a unified explanation of mRNA variability for various experimental systems. From this analysis, we construct a quantitative model of transcription dynamics enabling analytic predictions for the dependence of mRNA noise on the mRNA lifetime distribution, confirmed against stochastic simulation. This work suggests promising new directions for quantitative investigation into cellular control over biological functions by making complex dynamics of intracellular reactions accessible to rigorous mathematical deductions.

PMID: 29352116 [PubMed - in process]



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Cardiolipin synthesizing enzymes form a complex that interacts with cardiolipin-dependent membrane organizing proteins.

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Cardiolipin synthesizing enzymes form a complex that interacts with cardiolipin-dependent membrane organizing proteins.

Biochim Biophys Acta. 2018 04;1863(4):447-457

Authors: Serricchio M, Vissa A, Kim PK, Yip CM, McQuibban GA

Abstract
The mitochondrial glycerophospholipid cardiolipin plays important roles in mitochondrial biology. Most notably, cardiolipin directly binds to mitochondrial proteins and helps assemble and stabilize mitochondrial multi-protein complexes. Despite their importance for mitochondrial health, how the proteins involved in cardiolipin biosynthesis are organized and embedded in mitochondrial membranes has not been investigated in detail. Here we show that human PGS1 and CLS1 are constituents of large protein complexes. We show that PGS1 forms oligomers and associates with CLS1 and PTPMT1. Using super-resolution microscopy, we observed well-organized nanoscale structures formed by PGS1. Together with the observation that cardiolipin and CLS1 are not required for PGS1 to assemble in the complex we predict the presence of a PGS1-centered cardiolipin-synthesizing scaffold within the mitochondrial inner membrane. Using an unbiased proteomic approach we found that PGS1 and CLS1 interact with multiple cardiolipin-binding mitochondrial membrane proteins, including prohibitins, stomatin-like protein 2 and the MICOS components MIC60 and MIC19. We further mapped the protein-protein interaction sites between PGS1 and itself, CLS1, MIC60 and PHB. Overall, this study provides evidence for the presence of a cardiolipin synthesis structure that transiently interacts with cardiolipin-dependent protein complexes.

PMID: 29343430 [PubMed - indexed for MEDLINE]



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