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PubMed1998

Three alternatively spliced mouse slow skeletal muscle troponin T isoforms: conserved primary structure and regulated expression during postnatal development.

We have cloned and sequenced full-length cDNAs encoding mouse slow skeletal muscle troponin T (sTnT). Alternative mRNA splicing-generated two high Mr isoforms and one low Mr sTnT isoform differing in the NH2-terminal primary structure have been identified by Western blotting, reverse transcription-polymerase chain reaction and cDNA cloning/expression analyses. Together with a 5'-alternative exon that was also found in human sTnT encoding an 11-amino-acid acidic segment, the results revealed a novel alternative splicing pathway to include or exclude a three-base segment to generate additional sTnT isoforms with NH2-terminal charge variations. Overriding the phylogenetic divergence, primary structure of sTnT is better conserved between mammalian and avian species than that of cardiac, fast and skeletal muscle TnTs from one species. Western blots demonstrate four expression patterns of sTnT during postnatal skeletal muscle development: (1) a decrease to a non-detectable level in mouse masseter, (2) an increase to become the sole TnT in sheep masseter, (3) an increase of the total level as well as the proportion of the low Mr isoform in sheep diaphragm and, (4) no significant change in total level or high/low Mr isoform ratio in sheep gastrocnemius. The highly conserved primary structure and fiber type-specific and developmentally regulated expression of sTnT indicate a physiological importance of this under-studied member of the TnT gene family.

Alternative Splicing↗
PubMed2005

A hairpin-like structure within an AU-rich mRNA-destabilizing element regulates trans-factor binding selectivity and mRNA decay kinetics.

In mammals, rapid mRNA turnover directed by AU-rich elements (AREs) is mediated by selective association of cellular ARE-binding proteins. These trans-acting factors display overlapping RNA substrate specificities and may act to either stabilize or destabilize targeted transcripts; however, the mechanistic features of AREs that promote preferential binding of one trans-factor over another are not well understood. Here, we describe a hairpin-like structure adopted by the ARE from tumor necrosis factor alpha (TNFalpha) mRNA that modulates its affinity for selected ARE-binding proteins. In particular, association of the mRNA-destabilizing factor p37(AUF1) was strongly inhibited by adoption of the higher order ARE structure, whereas binding of the inducible heat shock protein Hsp70 was less severely compromised. By contrast, association of the mRNA-stabilizing protein HuR was only minimally affected by changes in ARE folding. Consistent with the inverse relationship between p37(AUF1) binding affinity and the stability of ARE folding, mutations that stabilized the ARE hairpin also inhibited its ability to direct rapid mRNA turnover in transfected cells. Finally, phylogenetic analyses and structural modeling indicate that TNFalpha mRNA sequences flanking the ARE are highly conserved and may stabilize the hairpin fold in vivo. Taken together, these data suggest that local higher order structures involving AREs may function as potent regulators of mRNA turnover in mammalian cells by modulating trans-factor binding selectivity.

Base Sequence↗
PubMed2003

Phylogenetic analyses of potassium channel auxiliary subunits.

Results of recent genome-sequencing projects together with advances in biochemical, molecular genetic and physiological experimentation have allowed discovery of many transport auxiliary subunits. These subunits facilitate the proper movement of substrates across cell membranes. Mutations of any of these subunits can cause catastrophic effects to the transport mechanism and cause certain genetic diseases. Auxiliary subunits of ion channels are of particular interest because of their potential to diversify the transport properties of the principal subunits. Furthermore, ion channel auxiliary subunits may function in the capacity of enhancing surface expression, allowing gating, and providing chaperone-like activities. As a result of their evolutionary histories, these proteins can be grouped exclusively by phylogenetic techniques. Many of these families are found to be restricted to a single kingdom of life while others seem to be ubiquitous. Here we report the results of systematic analyses of three families of ion channel auxiliary subunits. Some subunits contain one or more transmembrane segments while others exist only in the cytoplasm. We have also observed potential horizontal transfer across kingdoms with these auxiliary subunits. In this report, we present tabulated results of homology searches, partial multiple alignments, secondary structure analyses, and phylogenetic trees for these families.

Animals↗
PubMed2006

A hexapod nuclear SSU rRNA secondary-structure model and catalog of taxon-specific structural variation.

RNA molecules and in particular the nuclear SSU RNA play an important role in molecular systematics. With the advent of increasingly parameterized substitution models in systematic research, the incorporation of secondary-structure information became a realistic option compensating interdependence of character variation. As a prerequisite, consensus structures of eukaryotic SSU RNA molecules have become available through extensive comparative analyses and crystallographic studies. Despite extensive research in hexapod phylogenetics, consensus SSU RNA secondary structures focusing on hexapods have not yet been explored. In this study, we compiled a representative hexapod SSU data set of 261 sequences and inferred a specific consensus SSU secondary-structure model. Our search for conserved structural motives relied on a combined approach of thermodynamic and covariation analyses. The hexapod consensus-structure model deviates from the canonical eukaryotic model in a number of helices. Additionally, in several helices the hexapod sequences did not support a single consensus structure. We provide consensus structures of these sections of single less-inclusive taxa, thus facilitating the adaptation of the consensus hexapod model to less-inclusive phylogenetic questions. The secondary-structure catalog will foster the application of RNA structure models in phylogenetic analyses using the SSU rRNA molecule, and it will improve the realism of substitution models and the reliability of reconstructions based on rRNA sequences.

Animals↗
PubMed1979

Fine structural localization of endogeneous peroxidase in the endostyle of ascidians, Ciona intestinalis. A part of phylogenetic studies of the thyroid gland.

The fine structural localization of peroxidase activity in the endostyle of Ciona intestinalis was studied by cytochemistry at electron microscopic level. Only zone 7 cells in this organ are positive for this enzyme activity. The reaction product is recognized in the external surface of the apical plasma membrane, and in the cisternae of the rough endoplasmic reticulum, of the nuclear envelope, and of the Golgi lamellae, and small vesicles of the Golgi region and of the apical cytoplasm. By electron microscopic autoradiography of 125I, the main site of iodination of thyroglobulin-like protein is considered to be the apical plasma membrane region of the zone 7 cells. The possibility of iodination of protein taking place within the endostylar lumen near the zone 7 cell cannot be ruled out. The relationship between the fine-structural localization of peroxidase activity and the site of iodination of protein is discussed.

Animals↗
PubMed1992

Structural rearrangements of the chloroplast genome provide an important phylogenetic link in ferns.

The chloroplast genome of most land plants is highly conserved. In contrast, physical and gene mapping studies have revealed a highly rearranged chloroplast genome in species representing four families of ferns. In all four, there has been a rare duplication of the psbA gene and the order of the psbA, 16S, and 23S rRNA genes has been inverted. Our analysis shows that the described rearrangement results from a minimum of two inversions within the inverted repeat. This chloroplast DNA structure provides unambiguous evidence that phylogenetically links families of ferns once thought to belong to different major evolutionary lineages.

Chloroplasts↗
PubMed1991

Histochemical study of aldehyde dehydrogenase in the rat CNS.

A quantitative histochemical method was developed to determine aldehyde dehydrogenase (EC 1.2.1.3; ALDH) activity in the CNS. The distribution of ALDH activity in all rat brain and spinal cord regions is described. Among the CNS neuron structures, high enzyme activity was found in receptor and effector neurons, whereas low activity was noted in perikarya of the majority of intermediate neurons, including all aminergic neurons. A positive correlation was demonstrated between the distribution of ALDH activity among rat CNS microregions (our own data) and the density of dopaminergic terminals, dopamine content, and monoamine oxidase activity (literature data) among the same microregions. They may reflect a spatial linkage between ALDH and the predicted sites of natural aldehyde production. Lower enzyme activity was found in phylogenetically younger brain structures. It may explain the differential resistance of CNS structures to ethanol (acetaldehyde). Among the barrier CNS structures, moderate ALDH activity was found in capillaries and surrounding astrocytes and high activity was noted in ependimocytes covering the brain cavities and those of the vascular plexus. This provides realization of the function of ALDH as a brain metabolic barrier for aldehydes.

Acetaldehyde↗
PubMed2005

Designing thermostable proteins: ancestral mutants of 3-isopropylmalate dehydrogenase designed by using a phylogenetic tree.

We have recently developed a new method for designing thermostable proteins using phylogenetic trees of enzymes. In this study, we investigated a method for designing proteins with improved stability using 3-isopropylmalate dehydrogenase (IPMDH) from Thermus thermophilus as a model enzyme. We designed 12 mutant enzymes, each having an ancestral amino acid residue that was present in the common ancestor of Bacteria and Archaea. At least six of the 12 ancestral mutants tested showed thermal stability higher than that of the original enzyme. The results supported the hyperthermophilic universal ancestor hypothesis. The effect of ancestral residues on IPMDHs of several organisms and on the related enzyme isocitrate dehydrogenase was summarised and analysed. The effect of an ancestral residue on thermostability did not depend on the degree of conservation of the residue at the site, suggesting that the stabilisation of these mutant proteins is not related to sequence conservation but to the antiquity of the introduced residues. The results suggest also that this method could be an efficient way of designing mutant enzymes with higher thermostability based only on the primary structure and a phylogenetic tree.

3-Isopropylmalate Dehydrogenase↗
PubMed1999

Molecular characterisation of the Arabidopsis SBP-box genes.

The Arabidopsis thaliana SPL gene family represents a group of structurally diverse genes encoding putative transcription factors found apparently only in plants. The distinguishing characteristic of the SPL gene family is the SBP-box encoding a conserved protein domain of 76 amino acids in length, the SBP-domain, which is responsible for the interaction with DNA. We present here characterisation of 12 members of the SPL gene family. These genes show highly diverse genomic organisations and are found scattered over the Arabidopsis genome. Some SPL genes are constitutively expressed, while transcriptional activity of others is under developmental control. Based on phylogenetic reconstruction, gene structure and expression patterns, they can be divided into subfamilies. In addition to the Arabidopsis SPL genes, we isolated and determined the sequences of three SBP-box genes from Antirrhinum majus and seven from Zea mays.

Amino Acid Motifs↗
PubMed1988

Heterochrony and human malformation.

The role of altered developmental timing or heterochrony in morphologic evolution has intrigued classical and modern biologists. Analogous manifestations of developmental asynchrony occur in human dysmorphogenesis where they illustrate the residue and repertoire of phylogenetic change. Certain single malformations such as holoprosencephaly immediately suggest heterochrony by their resemblance to antecedent phylogenetic or embryologic structures. Multiple malformation syndromes of genetic, chromosomal, or teratogenic etiology may have altered developmental timing as an underlying theme. The persisting alpha-fetoprotein synthesis in ataxia-telangiectasia, the morphologic atavisms in Down or trisomy 13 syndromes, and the delayed growth or fetal to adult hemoglobin switch in diabetic embryopathy all exemplify developmental asynchrony. The perspective of heterochrony stresses the molecular history and hierarchy which is recapitulated with each pregnancy, and reconciles apparent discrepancies between the rates of molecular and morphologic evolution. Recognition of heterochrony places isolated anomalies in the context of pattern and suggests monitoring of teratogenesis through altered expression of ontogenetically regulated, phylogenetically relevant molecules.

Aneuploidy↗
PubMed2004

Phylogenetic constraints and adaptation explain food-web structure.

Food webs are descriptions of who eats whom in an ecosystem. Although extremely complex and variable, their structure possesses basic regularities. A fascinating question is to find a simple model capturing the underlying processes behind these repeatable patterns. Until now, two models have been devised for the description of trophic interactions within a natural community. Both are essentially based on the concept of ecological niche, with the consumers organized along a single niche dimension; for example, prey size. Unfortunately, they fail to describe adequately recent and high-quality data. Here, we propose a new model built on the hypothesis that any species' diet is the consequence of phylogenetic constraints and adaptation. Simple rules incorporating both concepts yield food webs whose structure is very close to real data. Consumers are organized in groups forming a nested hierarchy, which better reflects the complexity and multidimensionality of most natural systems.

Adaptation, Physiological↗
PubMed2002

Cyclophilins, a new family of cross-reactive allergens.

Type I allergic reactions occur by immediate release of anaphylactogenic mediators due to cross-linking of IgE bound to the high-affinity Fc(epsilon)RI on the surface of effector cells of sensitized individuals after allergen exposure. IgE-mediated hypersensitivity against normally innocuous environmental antigens is of clinical importance because of an increasing incidence of asthma and severe atopic diseases causing raising health care burdens to the society. A vast variety of different molecular structures has been shown to be able to induce hypersensitivity reactions. However, the high structural homology between phylogenetically conserved allergenic proteins present in different, apparently unrelated sources of exposure seems to play an important role in IgE-mediated poly-sensitization. These allergen families, formally termed pan-allergens, represent proteins sharing a high degree of sequence homology. Here we report cloning, production and serological investigations of a new pan-allergen family, the cyclophilins, found to be cross-reactive across species including humans. IgE-mediated cross-reactivity against autoantigens may contribute to perpetuation of severe atopic disorders even in the absence of exogenous allergen exposure. The molecular definition of pan-allergen families may substantially contribute to reduce the number of structures needed for diagnosis and therapy of allergic diseases based on highly pure, standardized recombinant allergens.

Allergens↗
PubMed1991

Mammalian hexokinase 1: evolutionary conservation and structure to function analysis.

We have amplified and sequenced the complete coding region of bovine hexokinase isoenzyme 1 (HK1) from brain RNA with PCR primers selected for sequence conservation. The sequence information was analyzed to evaluate the evolutionary and structure-function relationships among the mammalian and yeast HK isoenzymes. Structure to function analysis identified an unduplicated, invariant N-terminal domain involved in HK1 outer mitochondrial membrane targeting, as well as putative carbohydrate and nucleotide-binding sites in the regulatory and catalytic halves of HK1 essential to enzyme function. The ATP-binding site in the catalytic half of the HK1 protein resembles nucleotide-binding regions from protein kinases, with the single amino acid replacement (lysine to glutamate) in the ATP-binding site of the amino half explaining the loss of HK1 catalytic function in the regulatory domain. Sequence comparisons suggest that the 50-kDa mammalian and yeast glucokinases arose separately in evolution. In addition to providing valuable phylogenetic and structure-function insights, this work provides an efficient strategy for rapid cloning and sequencing of the coding regions for other HKs and related proteins.

Amino Acid Sequence↗
PubMed1996

Phylogenetic occurrence of coiled coil proteins: implications for tissue structure in metazoa via a coiled coil tissue matrix.

We examined GenBank sequence files with a heptad repeat analysis program to assess the phylogenetic occurrence of coiled coil proteins, how heptad repeat domains are organized within them, and what structural/functional categories they comprise. Of 102,007 proteins analyzed, 5.95% (6,074) contained coiled coil domains; 1.26% (1,289) contained "extended" (> 75 amino acid) domains. While the frequency of proteins containing coiled coils was surprisingly constant among all biota, extended coiled coil proteins were fourfold more frequent in the animal kingdom and may reflect early events in the divergence of plants and animals. Structure/function categories of extended coils also revealed phylogenetic differences. In pathogens and parasites, many extended coiled coil proteins are external and bind host proteins. In animals, the majority of extended coiled coil proteins were identified as constituents of two protein categories: 1) myosins and motors; or 2) components of the nuclear matrix-intermediate filament scaffold. This scaffold, produced by sequential extraction of epithelial monolayers in situ, contains only 1-2% of the cell mass while accurately retaining morphological features of living epithelium and is greatly enriched in proteins with extensive, interrupted coiled coil forming domains. The increased occurrence of this type of protein in metazoa compared with plants or protists leads us to hypothesize a tissue-wide matrix of coiled coil interactions underlying metazoan differentiated cell and tissue structure.

Animals↗
PubMed1997

Phylogenetic analysis of membrane trafficking proteins: a family reunion and secondary structure predictions.

The realization that a highly conserved family of membrane proteins are localized to transport vesicles and selectively interact with proteins anchored at appropriate target sites of membrane fusion inspired a simple and compelling explanation of how proteins might be transferred and segregated within the cell, the "SNARE hypothesis". This model holds that vesicle and target membrane proteins (designated as v-SNARE and t-SNARE proteins, respectively) wind around one another to form a three-stranded coiled coil structure, termed the prefusion complex. While the molecular topology of the prefusion complex has not been established, the concept that phylogenetically diverse SNARE proteins may become interlocked in a stable coiled coil is particularly attractive, because such a tertiary fold would only be permitted between strictly matched binding partners. For this reason, we have performed a phenetic analysis of all known SNARE sequences to assess the evolutionary and structural relatedness of these ancient protein families. Our phylogenetic analysis and consensus structure predictions revealed that syntaxin and SNAP-25 homologs are significantly related and constitute a superfamily of t-SNARE proteins that fall naturally into four major classes with distinct architectural motifs. The synaptobrevins sorted into three different classes of v-SNARE proteins. Comparison of the consensus structure predictions within each lineage or class of SNARE proteins strongly implied that coiled coil domains may not be required for fusion complex assembly in simple eukaryotic cells. It is our hypothesis that SNARE proteins in the late secretory pathway of mammalian cells may have elaborated more complex secondary structures (coiled coils), at about the time metazoan organisms diverged from yeast, that provide a sterically rigid foundation for positioning a conserved binding domain, the amphipathic alpha-helix.

Animals↗
PubMed2004

[The ontogeny and physiology confirms the dual nature of sleep states].

In the Jouvet's laboratory, as early as 1960 the study of the ontogenesis of paradoxical sleep (PS) named "sleep 'with jerks" began in the kitten and led to the first publication in 1961. Then, several species were studied, lamb, rat, human neonates, etc. These works showed that at birth sleep with jerks was preponderant in altricial (immature) species (cat, rat) and the first to appear during the second half of gestation in precocious species (guinea pig). For Jouvet, sleep with jerks is a immature form of PS. Why PS is so important at birth? The maturation of the central nervous system, based on the myelinization, starts in the spinal cord then forwards to the brainstem and forebrain. So, PS mechanisms located in the brainstem are the first to mature and the only one to function. Then the slow wave sleep (SWS) and waking structures become mature. Phylogenetic studies showed that in mammals and birds PS was present even in marsupials and monotremes. Until now only the one exception is the dolphin with a voluntary breathing. To sleep and breath, dolphin has developed an unilateral sleep without classical PS. In other animals, reptiles, amphibians, fishes, PS was not observed with the parameters used in mammals. The study at birth (not yet done) of reptiles would allow perhaps the observation of a temporary PS. Based on these findings, a schematic model of the sleep regulation can be elaborated. Haeckel's aphorism "Ontogeny recapitulates phylogeny" seems true for PS which appears in birds and mammals i.e. at the end of evolution as it appears at the end of gestation when PS cerebral structures are present and mature.

Animals↗
PubMed2006

Highly conserved caspase and Bcl-2 homologues from the sea anemone Aiptasia pallida: lower metazoans as models for the study of apoptosis evolution.

Key insight into the complexities of apoptosis may be gained from the study of its evolution in lower metazoans. In this study we describe two genes from a cnidarian, Aiptasia pallida, that are homologous to key genes in the apoptotic pathway from vertebrates. The first is a novel ancient caspase, acasp, that displays attributes of both initiator and executioner caspases and includes a caspase recruitment domain (CARD). The second, a Bcl-2 family member, abhp, contains a BH1 and BH2 domain and shares structural characteristics and phylogenetic affinity with a group of antiapoptotic Bcl-2s including A1 and Bcl-2L10. The breadth of occurrence of other invertebrate homologues across the phylogenetic trees of both genes suggests that the complexity of apoptotic pathways is an ancient trait that predates the evolution of vertebrates and higher invertebrates such as nematodes and flies. This paves the way for establishing new lower metazoan model systems for the study of apoptosis.

Amino Acid Sequence↗
PubMed1996

Three-dimensional structure analysis of mu-agatoxins: further evidence for common motifs among neurotoxins with diverse ion channel specificities.

We report the solution structure of mu-agatoxin-I (mu-Aga-I) and model structures of the closely related mu-agatoxin-IV (mu-Aga-IV) which were isolated from venom of the American funnel web spider, Agelenopsis aperta. These toxins, which modify the kinetics of neuronal voltage-activated sodium channels in insects, are C-terminally amidated peptides composed to 36 amino acids, including four internal disulfide bonds. The structure of mu-Aga-I was determined by NMR and distance geometry/molecular dynamics calculations. Structural calculations were carried out using 256 interresidue NOE-derived distance restraints and 25 angle restraints obtained from vicinal coupling constants. The peptide contains eight cysteines involved in disulfide bonds, the pairings of which were uncertain and had to be determined from preliminary structure calculations. The toxin has an average rmsd of 0.89 A for the backbone atoms among 38 converged conformers. The structure consists of a well-defined triple-stranded beta-sheet involving residues 7-9, 20-24, and 30-34 and four tight turns. A homologous peptide, mu-Aga-IV, exhibited two distinct and equally populated conformations in solution, which complicated spectral analysis. Analysis of sequential NOE's confirmed that the conformers arose from cis and trans peptide bonds involving a proline at position 15. Models were developed for both conformers based on the mu-Aga-I structure. Our structural data show that the mu-agatoxins, although specific modifiers of sodium channels, share common secondary and tertiary structural motifs with phylogenetically diverse peptide toxins targeting a variety of channel types. The mu-agatoxins add voltage-sensitive sodium channel activity to a growing list of neurotoxic effects elicited by peptide toxins which share the same global fold yet differ in their animal origin and ion channel selectivity.

Agatoxins↗