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At least 1,531 records · Page 85Linked to original sources
PubMed2006

Ab initio genotype-phenotype association reveals intrinsic modularity in genetic networks.

Microbial species express an astonishing diversity of phenotypic traits, behaviors, and metabolic capacities. However, our molecular understanding of these phenotypes is based almost entirely on studies in a handful of model organisms that together represent only a small fraction of this phenotypic diversity. Furthermore, many microbial species are not amenable to traditional laboratory analysis because of their exotic lifestyles and/or lack of suitable molecular genetic techniques. As an adjunct to experimental analysis, we have developed a computational information-theoretic framework that produces high-confidence gene-phenotype predictions using cross-species distributions of genes and phenotypes across 202 fully sequenced archaea and eubacteria. In addition to identifying the genetic basis of complex traits, our approach reveals the organization of these genes into generic preferentially co-inherited modules, many of which correspond directly to known enzymatic pathways, molecular complexes, signaling pathways, and molecular machines.

Bacteria↗
PubMed2005

Combinatorial polyketide biosynthesis by de novo design and rearrangement of modular polyketide synthase genes.

Type I polyketide synthase (PKS) genes consist of modules approximately 3-6 kb long, which encode the structures of 2-carbon units in polyketide products. Alteration or replacement of individual PKS modules can lead to the biosynthesis of 'unnatural' natural products but existing techniques for this are time consuming. Here we describe a generic approach to the design of synthetic PKS genes where facile cassette assembly and interchange of modules and domains are facilitated by a repeated set of flanking restriction sites. To test the feasibility of this approach, we synthesized 14 modules from eight PKS clusters and associated them in 154 bimodular combinations spanning over 1.5-million bp of novel PKS gene sequences. Nearly half the combinations successfully mediated the biosynthesis of a polyketide in Escherichia coli, and all individual modules participated in productive bimodular combinations. This work provides a truly combinatorial approach for the production of polyketides.

Amino Acid Sequence↗
PubMed2006

Modular approaches to expanding the functions of living matter.

The synthesis of increasingly complex unnatural networks embedded in living matter is an emerging theme in synthetic biology. Synthetic networks have allowed the creation of organisms endowed with toggle switches, logic gates, pattern-forming systems, oscillators, cellular sensors, new modes of gene regulation and expanded genetic codes. A common challenge of this work is the addition of specific new functions to complex living organisms. This requires spatial and temporal control of molecular interactions and fluxes to achieve the desired outcomes. Here we review recent successes in this emerging field and discuss strategies for addressing the challenges of increasing network complexity.

Animals↗
PubMed2002

Revealing modular organization in the yeast transcriptional network.

Standard clustering methods can classify genes successfully when applied to relatively small data sets, but have limited use in the analysis of large-scale expression data, mainly owing to their assignment of a gene to a single cluster. Here we propose an alternative method for the global analysis of genome-wide expression data. Our approach assigns genes to context-dependent and potentially overlapping 'transcription modules', thus overcoming the main limitations of traditional clustering methods. We use our method to elucidate regulatory properties of cellular pathways and to characterize cis-regulatory elements. By applying our algorithm systematically to all of the available expression data on Saccharomyces cerevisiae, we identify a comprehensive set of overlapping transcriptional modules. Our results provide functional predictions for numerous genes, identify relations between modules and present a global view on the transcriptional network.

Algorithms↗
PubMed2002

Modular flexibility of dystrophin: implications for gene therapy of Duchenne muscular dystrophy.

Attempts to develop gene therapy for Duchenne muscular dystrophy (DMD) have been complicated by the enormous size of the dystrophin gene. We have performed a detailed functional analysis of dystrophin structural domains and show that multiple regions of the protein can be deleted in various combinations to generate highly functional mini- and micro-dystrophins. Studies in transgenic mdx mice, a model for DMD, reveal that a wide variety of functional characteristics of dystrophy are prevented by some of these truncated dystrophins. Muscles expressing the smallest dystrophins are fully protected against damage caused by muscle activity and are not morphologically different from normal muscle. Moreover, injection of adeno-associated viruses carrying micro-dystrophins into dystrophic muscles of immunocompetent mdx mice results in a striking reversal of histopathological features of this disease. These results demonstrate that the dystrophic pathology can be both prevented and reversed by gene therapy using micro-dystrophins.

Analysis of Variance↗
PubMed2003

Perceptual interference supports a non-modular account of face processing.

The perception of faces and of nonface objects share common early visual processing stages. Some argue, however, that the brain eventually processes faces separately from other objects, within a domain-specific module dedicated to face perception. This apparent specialization for faces could, alternatively, result from people's expertise with this category of stimuli. Here we used behavioral and electrophysiological measures of interference to address the functional independence of face and object processing. If the expert processing of faces and cars depend on common mechanisms related to holistic perception (obligatory processing of all parts), then for human subjects who are presumed to be face experts, car perception should interfere with concurrent face perception. Furthermore, such interference should increase with greater expertise in car identification, and indeed this is what we found. Event-related potentials (ERPs) suggest that this interference arose from perceptual processes contributing to the holistic processing of both objects of expertise and faces.

Adolescent↗
PubMed2006

Protein linguistics - a grammar for modular protein assembly?

The correspondence between biology and linguistics at the level of sequence and lexical inventories, and of structure and syntax, has fuelled attempts to describe genome structure by the rules of formal linguistics. But how can we define protein linguistic rules? And how could compositional semantics improve our understanding of protein organization and functional plasticity?

Linguistics↗
PubMed1997

The solution structure of a specific GAGA factor-DNA complex reveals a modular binding mode.

The structure of a complex between the DNA binding domain of the GAGA factor (GAGA-DBD) and an oligonucleotide containing its GAGAG consensus binding site has been determined by nuclear magnetic resonance spectroscopy. The GAGA-DBD comprises a single classical Cys2-His2 zinc finger core, and an N-terminal extension containing two highly basic regions, BR1 and BR2. The zinc finger core binds in the major groove and recognizes the first three GAG bases of the consensus in a manner similar to that seen in other classical zinc finger-DNA complexes. Unlike the latter, which require tandem zinc finger repeats with a minimum of two units for high affinity binding, the GAGA-DBD makes use of only a single finger complemented by BR1 and BR2. BR2 forms a helix that interacts in the major groove recognizing the last G of the consensus, while BR1 wraps around the DNA in the minor groove and recognizes the A in the fourth position of the consensus. The implications of the structure of the GAGA-DBD-DNA complex for chromatin remodelling are discussed.

Amino Acid Sequence↗
PubMed1997

Modular organization of the E2F1 activation domain and its interaction with general transcription factors TBP and TFIIH.

The transcriptional activator E2F1 regulates the expression of genes at the G1/S boundary. We have characterized interactions of the E2F1 activation domain with two general transcription factors, the TATA-box binding protein (TBP) and TFIIH. Two distinct binding sites on E2F1 were identified for TBP (amino acids 386-417 and 415-437) each of which supported activation in mammalian cells when expressed as a fusion to a heterologous DNA-binding domain. Neither of these minimal activation domains independently bound TFIIH; rather, the TFIIH binding site of E2F1 overlaps both domains. Loss of TFIIH-binding by E2F1 resulted in a 60-65% reduction in transactivation, suggesting that the E2F1/TFIIH interaction is important, but not essential, for transactivation. The retinoblastoma protein (Rb) binds directly to E2F1 and represses E2F1-mediated transactivation. We have demonstrated that recombinant Rb can compete with TBP and the p62 subunit of TFIIH for binding to immobilized E2F1. A tumorigenic form of Rb deficient in repressing E2F1-mediated transactivation is likewise deficient in displacing TBP from E2F1. We propose that competition between Rb and both TBP and TFIIH for binding to E2F1 is a mechanism by which Rb inhibits transactivation by E2F1.

Binding Sites↗
PubMed2004

The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture.

Neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4) is the prototypical protein in a family of E3 ubiquitin ligases that have a common domain architecture. They are comprised of a catalytic C-terminal HECT domain and N-terminal C2 domain and WW domains responsible for cellular localization and substrate recognition. These proteins are found throughout eukaryotes and regulate diverse biological processes through the targeted degradation of proteins that generally have a PPxY motif for WW domain recognition, and are found in the nucleus and at the plasma membrane. Whereas the yeast Saccharomyces cerevisiae uses a single protein, Rsp5p, to carry out these functions, evolution has provided higher eukaryotes with several related Nedd4 proteins that appear to have specialized roles. In this review we discuss how knowledge of individual domain function has provided insight into the physiological roles of the Nedd4 proteins and describe recent results that suggest discrete functions for individual family members.

Amino Acid Sequence↗
PubMed2001

Exploiting modularity in template-controlled synthesis: a new linear template to direct reactivity within discrete hydrogen-bonded molecular assemblies in the solid state.

Co-crystallization of 1,8-naphthalenedicarboxylic acid (1,8-nap) with trans-1,2-bis(n-pyridyl)ethylene (n,n'-bpe) (n = 2 or 4) yields a discrete four-component molecular assembly, 2(n,n'-bpe).2(1,8-nap) 1, that is held together by four O-H...N hydrogen bonds where the dicarboxylic acid, serving as a linear template, directs alignment of olefins in the solid state for [2 + 2] photoreaction.

Journal Article↗