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PubMed2006

A hybrid method for predicting the microstructure of polymers with complex architecture: combination of single-chain simulation with density functional theory.

A hybrid method is proposed to investigate the microstructure of various polymeric fluids confined between two parallel surfaces. The hybrid method combines a single-chain Monte Carlo (MC) simulation for the ideal-gas part of the Helmholtz energy and a density functional theory (DFT) for the excess part that arises from nonbonded intersegment interactions. The latter consists of a modified fundamental measure theory for excluded-volume effect, the first-order thermodynamics perturbation theory for chain connectivity, and a mean-field approximation for the van der Waals attraction. In comparison with a conventional DFT, the hybrid method avoids calculation of the time-consuming recursive functions and is directly applicable to polymers with arbitrary molecular architecture. Its numerical performance has been validated by extensive comparisons with MC data for the density distributions of totally flexible, semiflexible, or rigid polymers and those with starlike architecture. Special attention is also given to the formation of a nematic monolayer by rigid molecules laying perpendicular to a planar surface. The hybrid method predicts the surface pressure versus surface coverage in good agreement with experiment.

Journal Article↗
PubMed2004

The contribution of epistasis to the architecture of fitness in an RNA virus.

The tendency for genetic architectures to exhibit epistasis among mutations plays a central role in the modern synthesis of evolutionary biology and in theoretical descriptions of many evolutionary processes. Nevertheless, few studies unquestionably show whether, and how, mutations typically interact. Beneficial mutations are especially difficult to identify because of their scarcity. Consequently, epistasis among pairs of this important class of mutations has, to our knowledge, never before been explored. Interactions among genome components should be of special relevance in compacted genomes such as those of RNA viruses. To tackle these issues, we first generated 47 genotypes of vesicular stomatitis virus carrying pairs of nucleotide substitution mutations whose separated and combined deleterious effects on fitness were determined. Several pairs exhibited significant interactions for fitness, including antagonistic and synergistic epistasis. Synthetic lethals represented 50% of the latter. In a second set of experiments, 15 genotypes carrying pairs of beneficial mutations were also created. In this case, all significant interactions were antagonistic. Our results show that the architecture of the fitness depends on complex interactions among genome components.

Cloning, Molecular↗
PubMed2005

Molecular architecture and assembly mechanism of Drosophila tripeptidyl peptidase II.

In eukaryotes, tripeptidyl peptidase II (TPPII) is a crucial component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway. It is an amino peptidase belonging to the subtilase family removing tripeptides from the free N terminus of oligopeptides. The 150-kDa subunits of Drosophila TPPII assemble into a giant proteolytic complex of 6 MDa with a remarkable architecture consisting of two segmented and twisted strands that form a spindle-shaped structure. A refined 3D model has been obtained by cryoelectron microscopy, which reveals details of the molecular architecture and, in conjunction with biochemical data, provides insight into the assembly mechanism. The building blocks of this complex are apparently dimers, within which the 150-kDa monomers are oriented head to head. Stacking of these dimers leads to the formation of twisted single strands, two of which comprise the fully assembled spindle. This spindle also forms when TPPII is heterologously expressed in Escherichia coli, demonstrating that no scaffolding protein is required for complex formation and length determination. Reciprocal interactions of the N-terminal part of subunits from neighboring strands are probably involved in the formation of the native quaternary structure, lending the TPPII spindle a stability higher than that of single strands.

Aminopeptidases↗
PubMed2006

Simple fold composition and modular architecture of the nuclear pore complex.

The nuclear pore complex (NPC) consists of multiple copies of approximately 30 different proteins [nucleoporins (nups)], forming a channel in the nuclear envelope that mediates macromolecular transport between the cytosol and the nucleus. With <5% of the nup residues currently available in experimentally determined structures, little is known about the detailed structure of the NPC. Here, we use a combined computational and biochemical approach to assign folds for approximately 95% of the residues in the yeast and vertebrate nups. These fold assignments suggest an underlying simplicity in the composition and modularity in the architecture of all eukaryotic NPCs. The simplicity in NPC composition is reflected in the presence of only eight fold types, with the three most frequent folds accounting for approximately 85% of the residues. The modularity in NPC architecture is reflected in its hierarchical and symmetrical organization that partitions the predicted nup folds into three groups: the transmembrane group containing transmembrane helices and a cadherin fold, the central scaffold group containing beta-propeller and alpha-solenoid folds, and the peripheral FG group containing predominantly the FG repeats and the coiled-coil fold. Moreover, similarities between structures in coated vesicles and those in the NPC support our prior hypothesis for their common evolutionary origin in a progenitor protocoatomer. The small number of predicted fold types in the NPC and their internal symmetries suggest that the bulk of the NPC structure has evolved through extensive motif and gene duplication from a simple precursor set of only a few proteins.

Computational Biology↗
PubMed2006

The role of the proline-rich domain of Ssdp1 in the modular architecture of the vertebrate head organizer.

Lim1, Ssdp1, and Ldb1 proteins are components of the Ldb1-associated transcriptional complex, which is important in the head-organizing activity during early mouse development. Depletion of each individual protein alone causes a headless phenotype. To explore in more detail the modular architecture of the complex, we have generated two different gene-trapped mouse lines that express truncated forms of Ssdp1. Embryos derived from the gene-trapped line that encodes a truncated Ssdp1 lacking the proline-rich sequence exhibit a lethal abnormal head-development phenotype, resembling mouse embryos deficient for Lim1, Ssdp1, or Otx2 genes. Embryos derived from the second gene-trapped line, in which most of the proline-rich domain of Ssdp1 is retained, did not show abnormalities in head development. Our data demonstrate that components of the Ldb1-dependent module can be subdivided further into discrete functional domains and that the proline-rich stretch of Ssdp1 is critical for embryonic head development. Furthermore, phylogenetic comparisons revealed that in Caenorhabditis elegans, a similar proline-rich sequence is absent in Ssdp but present in Ldb1. We conclude that although the overall architecture of the Ldb1-dependent module has been preserved, the genetic specification of its individual components has diversified during evolution, without compromising the function of the module.

Amino Acid Sequence↗
PubMed2003

Genetic architecture and evolutionary constraint when the environment contains genes.

The environment provided by conspecifics is often the most important component of the environment experienced by individuals, frequently having profound effects on fitness and trait expression. Although these social effects on fitness and trait expression may appear to be purely environmental, they differ from other sorts of environmental influences, because they can have a genetic basis and thus can contribute to evolution. Theory has shown that these effects modify the definition of genetic architecture by making the phenotype the property of the genotypes of multiple individuals and alter evolutionary dynamics by introducing additional heritable components contributing to trait evolution. These effects suggest that genetic and evolutionary analyses of traits influenced by social environments must incorporate the genetic components of variation contributed by these environments. However, empirical studies incorporating these effects are generally lacking. In this paper, I quantify the contribution of genetically based environmental effects arising from social interactions during group rearing to the quantitative genetics of body size in Drosophila melanogaster. The results demonstrate that the genetic architecture of body size contains an important component of variation contributed by the social environment, which is hidden to ordinary genetic analyses and opposes the direct effects of genes on body-size development within a population. Using a model of trait evolution, I show that these effects significantly alter evolutionary predictions by providing hidden constraints on phenotypic evolution. The importance of relatedness of interactants and the potential impact of kin selection on the evolution of body size are also examined.

Animals↗
PubMed2002

The homeobox gene BREVIPEDICELLUS is a key regulator of inflorescence architecture in Arabidopsis.

Flowering plants display a remarkable range of inflorescence architecture, and pedicel characteristics are one of the key contributors to this diversity. However, very little is known about the genes or the pathways that regulate pedicel development. The brevipedicellus (bp) mutant of Arabidopsis thaliana displays a unique phenotype with defects in pedicel development causing downward-pointing flowers and a compact inflorescence architecture. Cloning and molecular analysis of two independent mutant alleles revealed that BP encodes the homeodomain protein KNAT1, a member of the KNOX family. bp-1 is a null allele with deletion of the entire locus, whereas bp-2 has a point mutation that is predicted to result in a truncated protein. In both bp alleles, the pedicels and internodes were compact because of fewer cell divisions; in addition, defects in epidermal and cortical cell differentiation and elongation were found in the affected regions. The downward-pointing pedicels were produced by an asymmetric effect of the bp mutation on the abaxial vs. adaxial sides. Cell differentiation, elongation, and growth were affected more severely on the abaxial than adaxial side, causing the change in the pedicel growth angle. In addition, bp plants displayed defects in cell differentiation and radial growth of the style. Our results show that BP plays a key regulatory role in defining important aspects of the growth and cell differentiation of the inflorescence stem, pedicel, and style in Arabidopsis.

Amino Acid Sequence↗
PubMed2003

Developmental gene regulatory network architecture across 500 million years of echinoderm evolution.

Evolutionary change in morphological features must depend on architectural reorganization of developmental gene regulatory networks (GRNs), just as true conservation of morphological features must imply retention of ancestral developmental GRN features. Key elements of the provisional GRN for embryonic endomesoderm development in the sea urchin are here compared with those operating in embryos of a distantly related echinoderm, a starfish. These animals diverged from their common ancestor 520-480 million years ago. Their endomesodermal fate maps are similar, except that sea urchins generate a skeletogenic cell lineage that produces a prominent skeleton lacking entirely in starfish larvae. A relevant set of regulatory genes was isolated from the starfish Asterina miniata, their expression patterns determined, and effects on the other genes of perturbing the expression of each were demonstrated. A three-gene feedback loop that is a fundamental feature of the sea urchin GRN for endoderm specification is found in almost identical form in the starfish: a detailed element of GRN architecture has been retained since the Cambrian Period in both echinoderm lineages. The significance of this retention is highlighted by the observation of numerous specific differences in the GRN connections as well. A regulatory gene used to drive skeletogenesis in the sea urchin is used entirely differently in the starfish, where it responds to endomesodermal inputs that do not affect it in the sea urchin embryo. Evolutionary changes in the GRNs since divergence are limited sharply to certain cis-regulatory elements, whereas others have persisted unaltered.

Animals↗
PubMed1986

From basic network principles to neural architecture: emergence of spatial-opponent cells.

The functional architecture of mammalian visual cortex has been elucidated in impressive detail by experimental work of the past 20-25 years. The origin of many of the salient features of this architecture, however, has remained unexplained. This paper is the first of three (the others will appear in subsequent issues of these Proceedings) that address the origin and organization of feature-analyzing (spatial-opponent and orientation-selective) cells in simple systems governed by biologically plausible development rules. I analyze the progressive maturation of a system composed of a few layers of cells, with connections that develop according to a simple set of rules (including Hebb-type modification). To understand the prenatal origin of orientation-selective cells in certain primates, I consider the case in which there is no external input, with the first layer exhibiting random spontaneous electrical activity. No orientation preference is specified to the system at any stage, and none of the basic developmental rules is specific to visual processing. Here I introduce the theory of "modular self-adaptive networks," of which this system is an example, and explicitly demonstrate the emergence of a layer of spatial-opponent cells. This sets the stage for the emergence, in succeeding layers, of an orientation-selective cell population.

Animals↗
PubMed1987

Molecular architecture of rabbit skeletal muscle aldolase at 2.7-A resolution.

The molecular architecture of the rabbit skeletal muscle aldolase (D-fructose-1,6-bisphosphate D-glyceraldehyde-3-phosphate-lyase, EC 4.1.2.13) tetramer has been determined to 2.7-A resolution. Solution of the three-dimensional structure of rabbit muscle aldolase utilized phase information from a single isomorphous Pt(CN)4(2-) derivative, which was combined with iterative-phase refinement based upon the noncrystallographic 222-fold symmetry exhibited by the tetramer subunits. The electron-density map calculated from the refined phases (mf = 0.72) was interpreted on the basis of the known amino acid sequence (363 amino acids per subunit). The molecular architecture of the aldolase subunit corresponds to a singly wound beta-barrel of the parallel alpha/beta class structures as has been observed in triose phosphate isomerase, pyruvate kinase, phosphogluconate aldolase, as well as others. Close contacts between tetramer subunits are virtually all between regions of hydrophobic residues. Contrary to other beta-barrel structures, the known active-site residues are located in the center of the beta-barrel and are accessible to substrate from the COOH side of the beta-barrel. Biochemical and crystallographic data suggest that the COOH-terminal region of aldolase covers the active-site pocket from the COOH side of the beta-barrel and mediates access to the active site. On the basis of sequence studies, active-site residues as well as residues lining the active-site pocket have been totally conserved throughout evolution. By comparison, homology in the COOH-terminal region is minimal. It is suggested that the amino acid sequence of the COOH-terminal region may be, in part, the basis for the variable specific activities aldolases exhibit toward their substrates.

Animals↗
PubMed1991

Architectural rules of the zinc-finger motif: comparative two-dimensional NMR studies of native and "aromatic-swap" domains define a "weakly polar switch".

The Zn-finger motif, encoding a globular minidomain with characteristic structure, provides a striking example of a sequence template for protein folding. Insight into architectural rules relating the amino acid sequence of a protein to its structure and stability may be obtained by comparative study of analogues. As our first step toward defining such rules for the Zn finger, we have recently described the design of an "aromatic-swap" analogue based on the ZFY two-finger repeat: a conserved alternation in sequence pattern observed among odd- and even-numbered domains in a family of sex-related vertebrate transcription factors. Consensus and "swapped" aromatic residues, introduced as revertants of less stable "aromaticless" analogues, were observed to provide equivalent contributions to the thermodynamic stability of the Zn finger. Here we describe and compare the solution structures of a wild-type domain and an aromatic-swap analogue, as determined by two-dimensional NMR and distance-geometry/restrained molecular dynamics calculations. The wild-type and aromatic-swap analogue each contain an N-terminal beta-sheet and a C-terminal alpha-helix (beta beta alpha motif), as observed in other systems, and exhibit a highly ordered hydrophobic core in which the native or swapped aromatic ring is closely packed. Remarkably, however, the two structures are stabilized by alternative aromatic-aromatic interactions, which in turn alter the respective DNA-binding surfaces. Our results suggest that native and swapped Zn-finger sequences encode a "weakly polar switch" between thermodynamically equivalent but functionally distinct architectures for DNA recognition.

Amino Acid Sequence↗
PubMed1995

Carbohydrate gluing, an architectural mechanism in the supramolecular structure of an annelid giant hemoglobin.

We report a carbohydrate-dependent supramolecular architecture in the extracellular giant hemoglobin (Hb) from the marine worm Perinereis aibuhitensis; we call this architectural mechanism carbohydrate gluing. This study is an extension of our accidental discovery of deterioration in the form of the Hb caused by a high concentration of glucose. The giant Hbs of annelids are natural supramolecules consisting of about 200 polypeptide chains that associate to form a double-layered hexagonal structure. This Hb has 0.5% (wt) carbohydrates, including mannose, xylose, fucose, galactose, glucose, N-acetylglucosamine (GlcNAc), and N-acetylgalactosamine (GalNAc). Using carbohydrate-staining assays, in conjunction with two-dimensional polyacrylamide gel electrophoresis, we found that two types of linker chains (L1 and L2; the nomenclature of the Hb subunits followed that for another marine worm, Tylorrhynchus heterochaetus) contained carbohydrates with both GlcNAc and GalNAc. Furthermore, two types of globins (a and A) have only GlcNAc-containing carbohydrates, whereas the other types of globins (b and B) had no carbohydrates. Monosaccharides including mannose, fucose, glucose, galactose, GlcNAc, and GalNAc reversibly dissociated the intact form of the Hb, but the removal of carbohydrate with N-glycanase resulted in irreversible dissociation. These results show that carbohydrate acts noncovalently to glue together the components to yield the complete quaternary supramolecular structure of the giant Hb. We suggest that this carbohydrate gluing may be mediated through lectin-like carbohydrate-binding by the associated structural chains ("linkers").

Amino Acid Sequence↗
PubMed1996

Architectural limits on split genes.

Exon/intron architecture varies across the eukaryotic kingdom with large introns and small exons the rule in vertebrates and the opposite in lower eukaryotes. To investigate the relationship between exon and intron size in pre-mRNA processing, internally expanded exons were placed in vertebrate genes with small and large introns. Both exon and intron size influenced splicing phenotype. Intron size dictated if large exons were efficiently recognized. When introns were large, large exons were skipped; when introns were small, the same large exons were included. Thus, large exons were incompatible for splicing if and only if they were flanked by large introns. Both intron and exon size became problematic at approximately 500 nt, although both exon and intron sequence influenced the size at which exons and introns failed to be recognized. These results indicate that present-day gene architecture reflects at least in part limitations on exon recognition. Furthermore, these results strengthen models that invoke pairing of splice sites during recognition of pre-mRNAs, and suggest that vertebrate consensus sequences support pairing across either introns or exons.

Adenine Phosphoribosyltransferase↗
PubMed1998

SMART, a simple modular architecture research tool: identification of signaling domains.

Accurate multiple alignments of 86 domains that occur in signaling proteins have been constructed and used to provide a Web-based tool (SMART: simple modular architecture research tool) that allows rapid identification and annotation of signaling domain sequences. The majority of signaling proteins are multidomain in character with a considerable variety of domain combinations known. Comparison with established databases showed that 25% of our domain set could not be deduced from SwissProt and 41% could not be annotated by Pfam. SMART is able to determine the modular architectures of single sequences or genomes; application to the entire yeast genome revealed that at least 6.7% of its genes contain one or more signaling domains, approximately 350 greater than previously annotated. The process of constructing SMART predicted (i) novel domain homologues in unexpected locations such as band 4.1-homologous domains in focal adhesion kinases; (ii) previously unknown domain families, including a citron-homology domain; (iii) putative functions of domain families after identification of additional family members, for example, a ubiquitin-binding role for ubiquitin-associated domains (UBA); (iv) cellular roles for proteins, such predicted DEATH domains in netrin receptors further implicating these molecules in axonal guidance; (v) signaling domains in known disease genes such as SPRY domains in both marenostrin/pyrin and Midline 1; (vi) domains in unexpected phylogenetic contexts such as diacylglycerol kinase homologues in yeast and bacteria; and (vii) likely protein misclassifications exemplified by a predicted pleckstrin homology domain in a Candida albicans protein, previously described as an integrin.

Amino Acid Sequence↗
PubMed1997

Chimeric erythropoietin-interferon gamma receptors reveal differences in functional architecture of intracellular domains for signal transduction.

Binding of interferon gamma (IFN-gamma) causes oligomerization of the two interferon gamma receptor (IFN-gammaR) subunits, receptor chain 1 (IFN-gammaR1, the ligand-binding chain) and the second chain of the receptor (IFN-gammaR2), and causes activation of two Jak kinases (Jak1 and Jak2). In contrast, the erythropoietin receptor (EpoR) requires only one receptor chain and one Jak kinase (Jak2). Chimeras between the EpoR and the IFN-gammaR1 and IFN-gammaR2 chains demonstrate that the architecture of the EpoR and the IFN-gammaR complexes differ significantly. Although IFN-gammaR1 alone cannot initiate signal transduction, the chimera EpoR/gammaR1 (extracellular/intracellular) generates slight responses characteristic of IFN-gamma in response to Epo and the EpoR/gammaR1. EpoR/gammaR2 heterodimer is a fully functional receptor complex. The results demonstrate that the configuration of the extracellular domains influences the architecture of the intracellular domains.

Humans↗
PubMed1998

Control of cell cycle progression by fibronectin matrix architecture.

Developmental patterning and differentiation, maintenance of parenchymal cell function, and the size, shape, and invasiveness of tumors are all orchestrated by cell interactions with the extracellular matrix. Here we show that the fibrillar structure of fibronectin (FN) matrix encodes essential regulatory cues and controls cell proliferation and signaling through changes in matrix architecture. A matrix assembled from native FN stimulated cell growth. In contrast, a mutant FN (FNDeltaIII1-7) that contains all known cell binding motifs but forms a structurally distinct matrix inhibited progression from G0/G1 into S phase. Furthermore, FNDeltaIII1-7 suppressed the stimulatory capacity of native FN and induced different levels of tyrosine phosphorylation of pp125(FAK). The differential effects on cell growth were ablated by blocking formation of matrix fibrils. Thus, modification of matrix architecture provides a novel approach to control cell proliferation.

Bromodeoxyuridine↗
PubMed1998

Thyroid hormone response element architecture affects corepressor release from thyroid hormone receptor dimers.

Thyroid hormone receptors are ligand-modulated transcription factors that can repress or activate transcription depending upon the absence or presence of thyroid hormone and the nature of the hormone response element to which the receptors are bound. The ability of thyroid hormone receptors to repress transcription in the absence of ligand is thought to be due to associations with nuclear hormone receptor corepressors. Ligand binding by the thyroid hormone receptor is believed to dissociate these corepressors and recruit coactivators to promote transcription from target promoters. We hypothesize that variations in response element architecture may influence both the association and dissociation of corepressors from DNA-bound thyroid hormone receptors. Using a chimeric corepressor, we find that ligand alone does not fully relieve corepressor-mediated repression, particularly in the presence of thyroid hormone receptor and its heterodimerization partner, the retinoid X receptor. Interestingly, the steroid receptor coactivator 1 together with ligand is able to mediate full release of corepression, but this relief is dependent upon the architecture of the response element to which the nuclear receptor dimer-corepressor complex is bound. These studies suggest that other cellular factors in addition to ligand may be required for the release of corepressors from thyroid hormone receptor dimers.

Dimerization↗
PubMed2001

Methylation-mediated silencing of TMS1/ASC is accompanied by histone hypoacetylation and CpG island-localized changes in chromatin architecture.

Aberrant methylation of CpG-dense islands in the promoter regions of genes is an acquired epigenetic alteration associated with the silencing of tumor suppressor genes in human cancers. In a screen for endogenous targets of methylation-mediated gene silencing, we identified a novel CpG island-associated gene, TMS1, which is aberrantly methylated and silenced in response to the ectopic expression of DNA methyltransferase-1. TMS1 functions in the regulation of apoptosis and is frequently methylated and silenced in human breast cancers. In this study, we characterized the methylation pattern and chromatin architecture of the TMS1 locus in normal fibroblasts and determined the changes associated with its progressive methylation. In normal fibroblasts expressing TMS1, the CpG island is defined by an unmethylated domain that is separated from densely methylated flanking DNA by distinct 5' and 3' boundaries. Analysis of the nucleoprotein architecture of the locus in intact nuclei revealed three DNase I-hypersensitive sites that map within the CpG island. Strikingly, two of these sites coincided with the 5'- and 3'-methylation boundaries. Methylation of the TMS1 CpG island was accompanied by loss of hypersensitive site formation, hypoacetylation of histones H3 and H4, and gene silencing. This altered chromatin structure was confined to the CpG island and occurred without significant changes in methylation, histone acetylation, or hypersensitive site formation at a fourth DNase I-hypersensitive site 2 kb downstream of the TMS1 CpG island. The data indicate that there are sites of protein binding and/or structural transitions that define the boundaries of the unmethylated CpG island in normal cells and that aberrant methylation overcomes these boundaries to direct a local change in chromatin structure, resulting in gene silencing.

Acetylation↗