CiteULike: cjeans's library [832 articles]

Darwinian Evolution on a Chip

Brian Paegel — 2008-04-25T18:53:31-00:00

PLoS Biology, Vol. 6, No. 4. (1 April 2008), e85.

Computer control of Darwinian evolution has been demonstrated by propagating a population of RNA enzymes in a microfluidic device. The RNA population was challenged to catalyze the ligation of an oligonucleotide substrate under conditions of progressively lower substrate concentrations. A microchip-based serial dilution circuit automated an exponential growth phase followed by a 10-fold dilution, which was repeated for 500 log-growth iterations. Evolution was observed in real time as the population adapted and achieved progressively faster growth rates over time. The final evolved enzyme contained a set of 11 mutations that conferred a 90-fold improvement in substrate utilization, coinciding with the applied selective pressure. This system reduces evolution to a microfluidic algorithm, allowing the experimenter to observe and manipulate adaptation.

Biologists initiate plan to map human proteome : Nature News

2008-04-24T14:32:59-00:00

Gene transcription: Two worlds merged

David Lonard — 2008-04-24T18:14:02-00:00

Nature, Vol. 452, No. 7190. (23 April 2008), pp. 946-947.

Getting Started in Text Mining

Bretonnel Cohen — 2008-01-30T03:27:37-00:00

PLoS Computational Biology, Vol. 4, No. 1. (1 January 2008), e20.

Mining literature for protein-protein interactions

Edward Marcotte — 2006-07-24T17:42:23-00:00

Bioinformatics, Vol. 17, No. 4. (1 April 2001), pp. 359-363.

Motivation: A central problem in bioinformatics is how to capture information from the vast current scientific literature in a form suitable for analysis by computer. We address the special case of information on protein-protein interactions, and show that the frequencies of words in Medline abstracts can be used to determine whether or not a given paper discusses protein-protein interactions. For those papers determined to discuss this topic, the relevant information can be captured for the Database of Interacting Proteins. Furthermore, suitable gene annotations can also be captured. Results: Our Bayesian approach scores Medline abstracts for probability of discussing the topic of interest according to the frequencies of discriminating words found in the abstract. More than 80 discriminating words (e.g. complex, interaction, two-hybrid) were determined from a training set of 260 Medline abstracts corresponding to previously validated entries in the Database of Interacting Proteins. Using these words and a log likelihood scoring function, [IMG]f1.gif" BORDER="0">2000 Medline abstracts were identified as describing interactions between yeast proteins. This approach now forms the basis for the rapid expansion of the Database of Interacting Proteins. Contact: marcotte@icmb.utexas.edu; ixenario@mbi.ucla.edu; david@mbi.ucla.edu 10.1093/bioinformatics/17.4.359

BioMed Central | Full text | PreBIND and Textomy – mining the biomedical literature for protein-protein interactions using a support vector machine

2008-03-19T02:52:13-00:00

Text-mining and information-retrieval services for molecular biology.

M Krallinger — 2005-08-14T15:07:32-00:00

Genome Biol, Vol. 6, No. 7. (2005)

Text-mining in molecular biology -- defined as the automatic extraction of information about genes, proteins and their functional relationships from text documents -- has emerged as a hybrid discipline on the edges of the fields of information science, bioinformatics and computational linguistics. A range of text-mining applications have been developed recently that will improve access to knowledge for biologists and database annotators.

Reassessing a sparse energetic network within a single protein domain

Celestine Chi — 2008-03-15T01:25:34-00:00

Proceedings of the National Academy of Sciences (13 March 2008), 0711732105.

Understanding the molecular principles that govern allosteric communication is an important goal in protein science. One way allostery could be transmitted is via sparse energetic networks of residues, and one such evolutionary conserved network was identified in the PDZ domain family of proteins by multiple sequence alignment [Lockless SW, Ranganathan R (1999) Science 286:295299]. We have reassessed the energetic coupling of these residues by double mutant cycles together with ligand binding and stability experiments and found that coupling is not a special property of the coevolved network of residues in PDZ domains. The observed coupling for ligand binding is better explained by a distance relationship, where residues close in space are more likely to couple than distal residues. Our study demonstrates that statistical coupling from sequence analysis is not necessarily a reporter of energetic coupling and allostery. 10.1073/pnas.0711732105

Using substitution probabilities to improve position-specific scoring matrices

Jorja Henikoff — 2008-03-15T01:22:24-00:00

Comput. Appl. Biosci., Vol. 12, No. 2. (1 April 1996), pp. 135-143.

Each column of amino acids in a multiple alignment of protein sequences can be represented as a vector of 20 amino acid counts. For alignment and searching applications, the count vector is an imperfect representation of a position, because the observed sequences are an incomplete sample of the full set of related sequences. One general solution to this problem is to model unobserved sequences by adding artificial pseudo-counts' to the observed counts. We introduce a simple method for computing pseudo-counts that combines the diversity observed in each alignment position with amino acid substitution probabilities. In extensive empirical tests, this position-based method out-performed other pseudo-count methods and was a substantial improvement over the traditional average score method used for constructing profiles. 10.1093/bioinformatics/12.2.135

Evaluation of methods for the prediction of membrane spanning regions.

S Möller — 2006-03-24T20:51:38-00:00

Bioinformatics, Vol. 17, No. 7. (July 2001), pp. 646-653.

MOTIVATION: A variety of tools are available to predict the topology of transmembrane proteins. To date no independent evaluation of the performance of these tools has been published. A better understanding of the strengths and weaknesses of the different tools would guide both the biologist and the bioinformatician to make better predictions of membrane protein topology. RESULTS: Here we present an evaluation of the performance of the currently best known and most widely used methods for the prediction of transmembrane regions in proteins. Our results show that TMHMM is currently the best performing transmembrane prediction program.

Domains, Motifs, and Scaffolds: The Role of Modular Interactions in the Evolution and Wiring of Cell Signaling Circuits.

Roby P Bhattacharyya — 2006-05-23T04:04:51-00:00

Annu Rev Biochem (17 March 2006)

Living cells display complex signal processing behaviors, many of which are mediated by networks of proteins specialized for signal transduction. Here we focus on the question of how the remarkably diverse array of eukaryotic signaling circuits may have evolved. Many of the mechanisms that connect signaling proteins into networks are highly modular: The core catalytic activity of a signaling protein is physically and functionally separable from molecular domains or motifs that determine its linkage to both inputs and outputs. This high degree of modularity may make these systems more evolvable-in principle, novel circuits, and therefore highly innovative regulatory behaviors, can arise from relatively simple genetic events such as recombination, deletion, or insertion. In support of this hypothesis, recent studies show that such modular systems can be exploited to engineer nonnatural signaling proteins and pathways with novel behavior. Expected online publication date for the Annual Review of Biochemistry Volume 75 is June 2, 2006. Please see http://www.annualreviews.org/catalog/pub_dates.asp for revised estimates.

Specificity in signal transduction: from phosphotyrosine-SH2 domain interactions to complex cellular systems.

T Pawson — 2008-01-29T02:43:37-00:00

Cell, Vol. 116, No. 2. (23 January 2004), pp. 191-203.

Over the last two decades, a new and unifying concept of cellular organization has emerged in which modular protein-protein interactions provide an underlying framework through which signaling pathways are assembled and controlled. In this scheme, posttranslational modifications such as phosphorylation commonly exert their biological effects by regulating molecular interactions, exemplified by the ability of phosphotyrosine sites to bind selectively to SH2 domains. Although these interactions are rather simple in isolation, they can nonetheless be exploited to generate complex cellular systems. Here, I discuss experiments that have led to this view of dynamic cellular behavior and identify some current and future areas of interest in cell signaling.

Oncogenic re-wiring of cellular signaling pathways

T Pawson — 2008-01-29T02:42:42-00:00

Oncogene, Vol. 26, No. 9. (0000), pp. 1268-1275.

The Frequency Dependence of Osmo-Adaptation in Saccharomyces cerevisiae

Jerome Mettetal — 2008-01-25T07:19:00-00:00

Science, Vol. 319, No. 5862. (25 January 2008), pp. 482-484.

The propagation of information through signaling cascades spans a wide range of time scales, including the rapid ligand-receptor interaction and the much slower response of downstream gene expression. To determine which dynamic range dominates a response, we used periodic stimuli to measure the frequency dependence of signal transduction in the osmo-adaptation pathway of Saccharomyces cerevisiae. We applied system identification methods to infer a concise predictive model. We found that the dynamics of the osmo-adaptation response are dominated by a fast-acting negative feedback through the kinase Hog1 that does not require protein synthesis. After large osmotic shocks, an additional, much slower, negative feedback through gene expression allows cells to respond faster to future stimuli. 10.1126/science.1151582

Alignment Uncertainty and Genomic Analysis

Karen Wong — 2008-01-25T07:09:02-00:00

Science, Vol. 319, No. 5862. (25 January 2008), pp. 473-476.

The statistical methods applied to the analysis of genomic data do not account for uncertainty in the sequence alignment. Indeed, the alignment is treated as an observation, and all of the subsequent inferences depend on the alignment being correct. This may not have been too problematic for many phylogenetic studies, in which the gene is carefully chosen for, among other things, ease of alignment. However, in a comparative genomics study, the same statistical methods are applied repeatedly on thousands of genes, many of which will be difficult to align. Using genomic data from seven yeast species, we show that uncertainty in the alignment can lead to several problems, including different alignment methods resulting in different conclusions. 10.1126/science.1151532

Concurrent Fast and Slow Cycling of a Transcriptional Activator at an Endogenous Promoter

Tatiana Karpova — 2008-01-25T07:02:07-00:00

Science, Vol. 319, No. 5862. (25 January 2008), pp. 466-469.

For gene regulation, some transcriptional activators bind periodically to promoters with either a fast ([~]1 minute) or a slow ([~]15 to 90 minutes) cycle. It is uncertain whether the fast cycle occurs on natural promoters, and the function of either cycle in transcription remains unclear. We report that fast and slow cycling can occur simultaneously on an endogenous yeast promoter and that slow cycling in this system reflects an oscillation in the fraction of accessible promoters rather than the recruitment and release of stably bound transcriptional activators. This observation, combined with single-cell measurements of messenger RNA (mRNA) production, argues that fast cycling initiates transcription and that slow cycling regulates the quantity of mRNA produced. These findings counter the prevailing view that slow cycling initiates transcription. 10.1126/science.1150559

GENOMICS: Lining Up to Avoid Bias

Antonis Rokas — 2008-01-25T06:50:52-00:00

Science, Vol. 319, No. 5862. (25 January 2008), pp. 416-417.

10.1126/science.1153156

SYSTEMS BIOLOGY: Enlightening Rhythms

Ovidiu Lipan — 2008-01-25T06:53:34-00:00

Science, Vol. 319, No. 5862. (25 January 2008), pp. 417-418.

10.1126/science.1154208

Maps of random walks on complex networks reveal community structure

Martin Rosvall — 2008-01-24T08:30:08-00:00

Proceedings of the National Academy of Sciences (23 January 2008), 0706851105.

To comprehend the multipartite organization of large-scale biological and social systems, we introduce an information theoretic approach that reveals community structure in weighted and directed networks. We use the probability flow of random walks on a network as a proxy for information flows in the real system and decompose the network into modules by compressing a description of the probability flow. The result is a map that both simplifies and highlights the regularities in the structure and their relationships. We illustrate the method by making a map of scientific communication as captured in the citation patterns of >6,000 journals. We discover a multicentric organization with fields that vary dramatically in size and degree of integration into the network of science. Along the backbone of the networkincluding physics, chemistry, molecular biology, and medicineinformation flows bidirectionally, but the map reveals a directional pattern of citation from the applied fields to the basic sciences. 10.1073/pnas.0706851105

The evolution of gene collectives: How natural selection drives chemical innovation

Michael Fischbach — 2008-01-24T08:27:07-00:00

Proceedings of the National Academy of Sciences (23 January 2008), 0709132105.

DNA sequencing has become central to the study of evolution. Comparing the sequences of individual genes from a variety of organisms has revolutionized our understanding of how single genes evolve, but the challenge of analyzing polygenic phenotypes has complicated efforts to study how genes evolve when they are part of a group that functions collectively. We suggest that biosynthetic gene clusters from microbes are ideal candidates for the evolutionary study of gene collectives; these selfish genetic elements evolve rapidly, they usually comprise a complete pathway, and they have a phenotypea small moleculethat is easy to identify and assay. Because these elements are transferred horizontally as well as vertically, they also provide an opportunity to study the effects of horizontal transmission on gene evolution. We discuss known examples to begin addressing two fundamental questions about the evolution of biosynthetic gene clusters: How do they propagate by horizontal transfer? How do they change to create new molecules? 10.1073/pnas.0709132105

Preferential protection of protein interaction network hubs in yeast: Evolved functionality of genetic redundancy

Ran Kafri — 2008-01-24T08:26:01-00:00

Proceedings of the National Academy of Sciences (23 January 2008), 0711043105.

The widely observed dispensability of duplicate genes is typically interpreted to suggest that a proportion of the duplicate pairs are at least partially redundant in their functions, thus allowing for compensatory affects. However, because redundancy is expected to be evolutionarily short lived, there is currently debate on both the proportion of redundant duplicates and their functional importance. Here, we examined these compensatory interactions by relying on a genome wide data analysis, followed by experiments and literature mining in yeast. Our data, thus, strongly suggest that compensated duplicates are not randomly distributed within the protein interaction network but are rather strategically allocated to the most highly connected proteins. This design is appealing because it suggests that many of the potentially vulnerable nodes that would otherwise be highly sensitive to mutations are often protected by redundancy. Furthermore, divergence analyses show that this association between redundancy and protein connectivity becomes even more significant among the ancient duplicates, suggesting that these functional overlaps have undergone purifying selection. Our results suggest an intriguing conclusion although redundancy is typically transient on evolutionary time scales, it tends to be preserved among some of the central proteins in the cellular interaction network. 10.1073/pnas.0711043105

Signal processing by its coil zipper domain activates IKKgamma

Stuart Bloor — 2008-01-24T06:52:37-00:00

Proceedings of the National Academy of Sciences (23 January 2008), 0706552105.

NF-kappaB activation occurs upon degradation of its inhibitor I-kappaB and requires prior phosphorylation of the inhibitor by I-kappaB kinase (IKK). Activity of IKK is governed by its noncatalytic subunit IKKgamma. Signaling defects due to missense mutations in IKKgamma have been correlated to its inability to either become ubiquitylated or bind ubiquitin noncovalently. Because the relative contribution of these events to signaling had remained unknown, we have studied mutations in the coil-zipper (CoZi) domain of IKKgamma that either impair signaling or cause constitutive NF-kappaB activity. Certain signaling-deficient alleles neither bound ubiquitin nor were they ubiquitylated by TRAF6. Introducing an activating mutation into those signaling-impaired alleles restored their ubiquitylation and created mutants constitutively activating NF-kappaB without repairing the ubiquitin-binding defect. Constitutive activity therefore arises downstream of ubiquitin binding but upstream of ubiquitylation. Such constitutive activity reveals a signal-processing function for IKKgamma beyond that of a mere ubiquitin-binding adaptor. We propose that this signal processing may involve homophilic CoZi interactions as suggested by the enhanced affinity of CoZi domains from constitutively active IKKgamma. 10.1073/pnas.0706552105

The Eps15 homology (EH) domain

Stefano Confalonieri — 2008-01-24T01:42:30-00:00

FEBS Letters, Vol. 513, No. 1. (20 February 2002), pp. 24-29.

The Eps15 homology (EH) domain was originally identified as a motif present in three copies at the NH2-termini of Eps15 and of the related molecule Eps15R. Both of these molecules are substrates for the tyrosine kinase activity of the epidermal growth factor receptor and hence the name `Eps15 homology' or EH domain [Wong et al. (1994) Oncogene 9, 1591-1597; Wong et al. (1995) Proc. Natl. Acad. Sci. USA 92, 9530-9534; Fazioli et al. (1993) Mol. Cell. Biol. 13, 5814-5828] was derived. The motif was subsequently found in several proteins from yeast to nematode, thus establishing its evolutionary conservation. Initial studies with filter-binding assays and phage-displayed libraries demonstrated its protein:protein interaction abilities and identified specific ligands. Subsequently, structural analyses established the molecular bases of recognition between EH domains and cognate peptides. To date, several EH-containing and EH-binding proteins have been identified, which establish in the cell a network of protein:protein interactions, defined as the EH network. This network coordinates cellular functions connected with endocytosis, actin remodeling and intracellular transduction of signals.

The ENTH domain

Pietro De Camilli — 2008-01-23T09:47:56-00:00

FEBS Letters, Vol. 513, No. 1. (20 February 2002), pp. 11-18.

The epsin NH2-terminal homology (ENTH) domain is a membrane interacting module composed by a superhelix of [alpha]-helices. It is present at the NH2-terminus of proteins that often contain consensus sequences for binding to clathrin coat components and their accessory factors, and therefore function as endocytic adaptors. ENTH domain containing proteins have additional roles in signaling and actin regulation and may have yet other actions in the nucleus. The ENTH domain is structurally similar to the VHS domain. These domains define two families of adaptor proteins which function in membrane traffic and whose interaction with membranes is regulated, in part, by phosphoinositides.

Reading protein modifications with interaction domains

Bruce Seet — 2006-06-28T17:44:42-00:00

Nature Reviews Molecular Cell Biology, Vol. 7, No. 7., pp. 473-483.

Critical nodes in signalling pathways: insights into insulin action

Cullen Taniguchi — 2006-01-24T21:36:39-00:00

Nat Rev Mol Cell Biol, Vol. 7, No. 2. (February 2006), pp. 85-96.

p53 in health and disease

Karen Vousden — 2007-03-24T18:09:51-00:00

Nature Reviews Molecular Cell Biology, Vol. 8, No. 4., pp. 275-283.

Dynamic control of signaling by modular adaptor proteins

Tony Pawson — 2007-03-12T19:54:32-00:00

Current Opinion in Cell Biology, Vol. In Press, Corrected Proof

Adaptor proteins are composed exclusively of domains and motifs that mediate molecular interactions, and can thereby link signaling proteins such as activated cell-surface receptors to downstream effectors. Recent data supports the notion that adaptors are not simply coupling devices that hard-wire successive components of signaling pathways. Rather, they display highly dynamic properties that direct the flow of information through signaling networks. The binding activity of adaptors can be regulated by conformational reorganization, and by the cooperative association of domains within the same adaptor. Furthermore, an individual adaptor can deliver different outputs by utilizing distinct combinations of binding partners. Adaptors can also control the oligomerization of receptor signaling complexes, and the subcellular location and duration of signaling events, and act as coincidence detectors to enhance specificity in cellular responses.

Effects of Molecular Memory and Bursting on Fluctuations in Gene Expression

Juan Pedraza — 2008-01-18T10:34:03-00:00

Science, Vol. 319, No. 5861. (18 January 2008), pp. 339-343.

Many cellular components are present in such low numbers per cell that random births and deaths of individual molecules can cause substantial "noise" in concentrations. But biochemical events do not necessarily occur in single steps of individual molecules. Some processes are greatly randomized when synthesis or degradation occurs in large bursts of many molecules during a short time interval. Conversely, each birth or death of a macromolecule could involve several small steps, creating a memory between individual events. We present a generalized theory for stochastic gene expression, formulating the variance in protein abundance in terms of the randomness of the individual gene expression events. We show that common types of molecular mechanisms can produce gestation and senescence periods that reduce noise without requiring higher abundances, shorter lifetimes, or any concentration-dependent control loops. We also show that most single-cell experimental methods cannot distinguish between qualitatively different stochastic principles, although this in turn makes such methods better suited for identifying which components introduce fluctuations. Characterizing the random events that give rise to noise in concentrations instead requires dynamic measurements with single-molecule resolution. 10.1126/science.1144331

Designed Protein-Protein Association

Dirk Grueninger — 2008-01-11T17:43:28-00:00

Science, Vol. 319, No. 5860. (11 January 2008), pp. 206-209.

The analysis of natural contact interfaces between protein subunits and between proteins has disclosed some general rules governing their association. We have applied these rules to produce a number of novel assemblies, demonstrating that a given protein can be engineered to form contacts at various points of its surface. Symmetry plays an important role because it defines the multiplicity of a designed contact and therefore the number of required mutations. Some of the proteins needed only a single side-chain alteration in order to associate to a higher-order complex. The mobility of the buried side chains has to be taken into account. Four assemblies have been structurally elucidated. Comparisons between the designed contacts and the results will provide useful guidelines for the development of future architectures. 10.1126/science.1150421

Pathways of clathrin-independent endocytosis

Satyajit Mayor — 2007-07-23T11:30:08-00:00

Nature Reviews Molecular Cell Biology, Vol. 8, No. 8., pp. 603-612.

Cancer and ageing: convergent and divergent mechanisms

Manuel Serrano — 2007-08-24T11:06:23-00:00

Nature Reviews Molecular Cell Biology, Vol. 8, No. 9., pp. 715-722.

Self-eating and self-killing: crosstalk between autophagy and apoptosis

Chiara Maiuri — 2007-08-24T11:06:23-00:00

Nature Reviews Molecular Cell Biology, Vol. 8, No. 9., pp. 741-752.

Concepts in sumoylation: a decade on

Ruth Geiss-Friedlander — 2007-11-26T13:23:27-00:00

Nat Rev Mol Cell Biol, Vol. 8, No. 12. (December 2007), pp. 947-956.

Palmitoylation: policing protein stability and traffic

Maurine Linder — 2006-12-21T08:11:08-00:00

Nature Reviews Molecular Cell Biology, Vol. 8, No. 1., pp. 74-84.

SUMO and ubiquitin in the nucleus: different functions, similar mechanisms?

Grace Gill — 2006-05-25T16:12:34-00:00

Genes Dev., Vol. 18, No. 17. (1 September 2004), pp. 2046-2059.

The small ubiquitin-related modifier SUMO posttranslationally modifies many proteins with roles in diverse processes including regulation of transcription, chromatin structure, and DNA repair. Similar to nonproteolytic roles of ubiquitin, SUMO modification regulates protein localization and activity. Some proteins can be modified by SUMO and ubiquitin, but with distinct functional consequences. It is possible that the effects of ubiquitination and SUMOylation are both largely due to binding of proteins bearing specific interaction domains. Both modifications are reversible, and in some cases dynamic cycles of modification may be required for activity. Studies of SUMO and ubiquitin in the nucleus are yielding new insights into regulation of gene expression, genome maintenance, and signal transduction. 10.1101/gad.1214604

Modification of Proteins by Ubiquitin and Ubiquitin-Like Proteins - Annual Review of Cell and Developmental Biology, 22(1):159 - Full Text

2008-01-23T02:21:27-00:00

Ubiquitin-binding domains

Linda Hicke — 2005-08-01T21:29:14-00:00

Nature Reviews Molecular Cell Biology, Vol. 6, No. 8. (01 August 2005), pp. 610-621.

Ubiquitin and ubiquitin-like proteins as multifunctional signals

Rebecca Welchman — 2005-08-01T21:29:14-00:00

Nature Reviews Molecular Cell Biology, Vol. 6, No. 8. (01 August 2005), pp. 599-609.

A superfamily of protein tags: ubiquitin, SUMO and related modifiers

David Schwartz — 2008-01-23T01:49:51-00:00

Trends in Biochemical Sciences, Vol. 28, No. 6. (June 2003), pp. 321-328.

The biological functions of many proteins are altered by their covalent attachment to polypeptide modifiers. The best-known example of this type of modification is ubiquitination. Ubiquitin has a well-documented role in targeting proteins for degradation by the proteasome, but additional effects of protein ubiquitination are now being uncovered. Furthermore, multiple polypeptides that are distinct from, but related to, ubiquitin are also enzymatically coupled to target macromolecules, and these ubiquitin-like proteins participate in diverse biological processes such as DNA repair, autophagy and signal transduction.

Back to the Future with Ubiquitin

Cecile Pickart — 2008-01-23T01:49:45-00:00

Cell, Vol. 116, No. 2. (23 January 2004), pp. 181-190.

Two papers published in 1984 by the Varshavsky laboratory revealed that the ubiquitin/proteasome pathway is the principal system for degradation of short-lived proteins in mammalian cells, setting the stage for future demonstrations of this pathway's many regulatory roles. This perspective discusses the impact of those papers and highlights some of the subsequent insights that have led to our current appreciation of the breadth of ubiquitin-mediated signaling.

Targeting Rab GTPases to distinct membrane compartments.

S Pfeffer — 2005-08-05T10:28:54-00:00

Nat Rev Mol Cell Biol, Vol. 5, No. 11. (November 2004), pp. 886-896.

Rab GTPases are key to membrane-trafficking events in eukaryotic cells, and human cells contain more than 60 Rab proteins that are localized to distinct compartments. The recent determination of the structure of a monoprenylated Rab GTPase bound to GDP-dissociation inhibitor provides new molecular details that are relevant to models of Rab delivery. The further discovery of an integral membrane protein that can dissociate prenylated Rab proteins from GDP-dissociation inhibitor gives new insights into the mechanisms of Rab localization.

Positive selection acting on splicing motifs reflects compensatory evolution

Shengdong Ke — 2008-01-22T00:42:12-00:00

Genome Res. (18 January 2008), gr.070268.107.

We have used comparative genomics to characterize the evolutionary behavior of predicted splicing regulatory motifs. Using base substitution rates in intronic regions as a calibrator for neutral change, we found a strong avoidance of synonymous substitutions that disrupt predicted exonic splicing enhancers or create predicted exonic splicing silencers. These results attest to the functionality of the hexameric motif set used and suggest that they are subject to purifying selection. We also found that synonymous substitutions in constitutive exon tend to create exonic splicing enhancers and to disrupt exonic splicing silencers, implying positive selection for these splicing promoting events. We present evidence that this positive selection is the result of splicing positive events compensating for splicing negative events as well as for mutations that weaken splice site sequences. Such compensatory events include non-synonymous mutations, synonymous mutations and mutations at splice sites. Compensation was also seen from the fact that orthologous exons tend to maintain the same number of predicted splicing motifs. Our data fit a splicing compensation model of exon evolution, in which selection for splicing positive mutations takes place to counter the effect of an ongoing splicing negative mutational process, with the exon as a whole being conserved as a unit of splicing. In the course of this analysis, we observed that synonymous positions in general are conserved relative to intronic sequences, suggesting that messenger RNA molecules are rich in sequence information for functions beyond protein coding and splicing 10.1101/gr.070268.107

Intracellular pattern recognition receptors in the host response

Etienne Meylan — 2006-07-07T14:40:52-00:00

Nature, Vol. 442, No. 7098., pp. 39-44.

Autophagosome formation: core machinery and adaptations

Zhiping Xie — 2007-10-15T20:17:57-00:00

Nat Cell Biol, Vol. 9, No. 10. (October 2007), pp. 1102-1109.

Autophagy: from phenomenology to molecular understanding in less than a decade

Daniel Klionsky — 2007-10-23T17:19:33-00:00

Nature Reviews Molecular Cell Biology, Vol. 8, No. 11., pp. 931-937.

The logic of indirect speech

Steven Pinker — 2008-01-17T09:51:20-00:00

Proceedings of the National Academy of Sciences (16 January 2008), 0707192105.

When people speak, they often insinuate their intent indirectly rather than stating it as a bald proposition. Examples include sexual come-ons, veiled threats, polite requests, and concealed bribes. We propose a three-part theory of indirect speech, based on the idea that human communication involves a mixture of cooperation and conflict. First, indirect requests allow for plausible deniability, in which a cooperative listener can accept the request, but an uncooperative one cannot react adversarially to it. This intuition is supported by a game-theoretic model that predicts the costs and benefits to a speaker of direct and indirect requests. Second, language has two functions: to convey information and to negotiate the type of relationship holding between speaker and hearer (in particular, dominance, communality, or reciprocity). The emotional costs of a mismatch in the assumed relationship type can create a need for plausible deniability and, thereby, select for indirectness even when there are no tangible costs. Third, people perceive language as a digital medium, which allows a sentence to generate common knowledge, to propagate a message with high fidelity, and to serve as a reference point in coordination games. This feature makes an indirect request qualitatively different from a direct one even when the speaker and listener can infer each other's intentions with high confidence. 10.1073/pnas.0707192105

Micromechanical properties of keratin intermediate filament networks

Sivaraj Sivaramakrishnan — 2008-01-17T09:46:48-00:00

Proceedings of the National Academy of Sciences (16 January 2008), 0710728105.

Keratin intermediate filaments (KIFs) form cytoskeletal KIF networks that are essential for the structural integrity of epithelial cells. However, the mechanical properties of the in situ network have not been defined. Particle-tracking microrheology (PTM) was used to obtain the micromechanical properties of the KIF network in alveolar epithelial cells (AECs), independent of other cytoskeletal components, such as microtubules and microfilaments. The storage modulus (G') at 1 Hz of the KIF network decreases from the perinuclear region (335 dyn/cm2) to the cell periphery (95 dyn/cm2), yielding a mean value of 210 dyn/cm2. These changes in G' are inversely proportional to the mesh size of the network, which increases approx10-fold from the perinuclear region (0.02 microm2) to the cell periphery (0.3 microm2). Shear stress (15 dyn/cm2 for 4 h) applied across the surface of AECs induces a more uniform distribution of KIF, with the mesh size of the network ranging from 0.02 microm2 near the nucleus to only 0.04 microm2 at the cell periphery. This amounts to a 40% increase in the mean G'. The storage modulus of the KIF network in the perinuclear region accurately predicts the shear-induced deflection of the cell nucleus to be 0.87 +/- 0.03 microm. The high storage modulus of the KIF network, coupled with its solid-like rheological behavior, supports the role of KIF as an intracellular structural scaffold that helps epithelial cells to withstand external mechanical forces. 10.1073/pnas.0710728105

The evolutionary dynamics of the Saccharomyces cerevisiae protein interaction network after duplication

Aviva Presser — 2008-01-17T08:38:46-00:00

Proceedings of the National Academy of Sciences (16 January 2008), 0707293105.

Gene duplication is an important mechanism in the evolution of protein interaction networks. Duplications are followed by the gain and loss of interactions, rewiring the network at some unknown rate. Because rewiring is likely to change the distribution of network motifs within the duplicated interaction set, it should be possible to study network rewiring by tracking the evolution of these motifs. We have developed a mathematical framework that, together with duplication data from comparative genomic and proteomic studies, allows us to infer the connectivity of the preduplication network and the changes in connectivity over time. We focused on the whole-genome duplication (WGD) event in Saccharomyces cerevisiae. The model allowed us to predict the frequency of intergene interaction before WGD and the post duplication probabilities of interaction gain and loss. We find that the predicted frequency of self-interactions in the preduplication network is significantly higher than that observed in today's network. This could suggest a structural difference between the modern and ancestral networks, preferential addition or retention of interactions between ohnologs, or selective pressure to preserve duplicates of self-interacting proteins. 10.1073/pnas.0707293105

High-confidence prediction of global interactomes based on genome-wide coevolutionary networks

David Juan — 2008-01-17T07:50:29-00:00

Proceedings of the National Academy of Sciences (16 January 2008), 0709671105.

Interacting or functionally related protein families tend to have similar phylogenetic trees. Based on this observation, techniques have been developed to predict interaction partners. The observed degree of similarity between the phylogenetic trees of two proteins is the result of many different factors besides the actual interaction or functional relationship between them. Such factors influence the performance of interaction predictions. One aspect that can influence this similarity is related to the fact that a given protein interacts with many others, and hence it must adapt to all of them. Accordingly, the interaction or coadaptation signal within its tree is a composite of the influence of all of the interactors. Here, we introduce a new estimator of coevolution to overcome this and other problems. Instead of relying on the individual value of tree similarity between two proteins, we use the whole network of similarities between all of the pairs of proteins within a genome to reassess the similarity of that pair, thereby taking into account its coevolutionary context. We show that this approach offers a substantial improvement in interaction prediction performance, providing a degree of accuracy/coverage comparable with, or in some cases better than, that of experimental techniques. Moreover, important information on the structure, function, and evolution of macromolecular complexes can be inferred with this methodology. 10.1073/pnas.0709671105