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PubMed2006

Evolutionally conserved intermediates between ubiquitin and NEDD8.

The investigation of common structural motifs provides additional information on why proteins conserve similar topologies yet may have non-conserved amino acid sequences. Proteins containing the ubiquitin superfold have similar topologies, although the sequence conservation is rather poor. Here, we present novel similarities and differences between the proteins ubiquitin and NEDD8. They have 57% identical sequence, almost identical backbone topology and similar functional strategy, although their physiological functions are mutually different. Using variable pressure NMR spectroscopy, we found that the two proteins have similar conformational fluctuation in the evolutionary conserved enzyme-binding region and contain a structurally similar locally disordered conformer (I) in equilibrium with the basic folded conformer (N). A notable difference between the two proteins is that the equilibrium population of I is far greater for NEDD8 (DeltaG(0)(NI)<5 kJ/mol) than for ubiquitin (DeltaG(0)(NI)=15.2(+/-1.0) kJ/mol), and that the tendency for overall unfolding (U) is also far higher for NEDD8 (DeltaG(0)(NU)=11.0(+/-1.5) kJ/mol) than for ubiquitin (DeltaG(0)(NU)=31.3(+/-4.7) kJ/mol). These results suggest that the marked differences in thermodynamic stabilities of the locally disordered conformer (I) and the overall unfolding species (U) are a key to determine the functional differences of the two structurally similar proteins in physiology.

Amino Acid Sequence↗
PubMed2000

Genetic analysis of ion channel dysfunction in Drosophila.

To dissect the molecular mechanisms of electrical activity in the nervous system, an extensive collection of mutations affecting various types of voltage-gated ion channels was identified and characterized in Drosophila. Most of these mutations were generated by chemical mutagenesis and were recognized on the basis of defects in motor behavior. These were the first genetically determined ion channelopathies to be characterized in any multicellular organism. Drosophila is a particularly attractive model system for such studies because of the availability of powerful genetic, electrophysiological, and molecular techniques for generating new mutations, characterizing their phenotypes, and cloning the genes thus defined. Consequently, a number of ion channels, including various types of K+ channels that had not yielded previously to biochemical approaches, were first identified via a genetic strategy in Drosophila. Evolutionary conservation of these genes enabled subsequent isolation of the corresponding genes from various mammals, including humans. Several of these human homologues have been found to be associated with heritable neuromuscular disorders. Studies of ion channel mutations in Drosophila have thus provided important biological information concerning the molecular and functional diversity of ion channels, their evolutionary relationships, and their in vivo functions in the nervous system. Similar studies of additional new mutations should now facilitate the analysis of ion channel regulatory mechanisms.

Animals↗
PubMed1997

Occurrence of plastid RNA editing in all major lineages of land plants.

RNA editing changes posttranscriptionally single nucleotides in chloroplast-encoded transcripts. Although much work has been done on mechanistic and functional aspects of plastid editing, little is known about evolutionary aspects of this RNA processing step. To gain a better understanding of the evolution of RNA editing in plastids, we have investigated the editing patterns in ndhB and rbcL transcripts from various species comprising all major groups of land plants. Our results indicate that RNA editing occurs in plastids of bryophytes, fern allies, true ferns, gymnosperms, and angiosperms. Both editing frequencies and editing patterns show a remarkable degree of interspecies variation. Furthermore, we have found that neither plastid editing frequencies nor the editing pattern of a specific transcript correlate with the phylogenetic tree of the plant kingdom. The poor evolutionary conservation of editing sites among closely related species as well as the occurrence of single species-specific editing sites suggest that the differences in the editing patterns and editing frequencies are probably due both to independent loss and to gain of editing sites. In addition, our results indicate that RNA editing is a relatively ancient process that probably predates the evolution of land plants. This supposition is in good agreement with the phylogenetic data obtained for plant mitochondrial RNA editing, thus providing additional evidence for common evolutionary roots of the two plant organellar editing systems.

Amino Acid Sequence↗
PubMed2001

GATA factors differentially activate multiple gonadal promoters through conserved GATA regulatory elements.

The GATA factors are a group of transcriptional regulators that play essential roles in cell differentiation, organ morphogenesis, and tissue-specific gene expression during development. The six vertebrate GATA factors are expressed in a broad spectrum of tissues, including the hemopoietic system, heart, gut, brain, placenta, pituitary, and gonads. Interestingly, GATA-like DNA-binding proteins are found in the gonads of several species, ranging from lower invertebrates to humans, thus supporting an evolutionary conserved and crucial role for these factors in gonadal development and function. Indeed, GATA factors are expressed from the onset of gonadal development and are later found in multiple cell lineages of both the testis and ovary. We now report that GATA-4 differentially activates transcription of several genes expressed in the gonads that encode either steroidogenic enzymes (steroidogenic acute regulatory protein and aromatase), hormones (inhibin alpha and Müllerian inhibiting substance) and a transcription factor (SF-1) known to be essential for gonadal development and function. Thus, our results identify GATA-4 as an important regulator of gonadal gene transcription where its specificity of action is mediated through synergistic interactions with other transcription factors such as SF-1.

Animals↗
PubMed1983

Conservation patterns of mouse "virus-like" (VL30) DNA sequences.

VL30 sequences are a murine dispersed multigene family with several "retrovirus-like" characteristics. Notably, they share basic structural features with retrovirus proviruses and 30S RNA transcripts of these genes are capable of efficient packaging in C-type virions and may be subsequently transmitted to other cells. It is not known whether VL30 information is genetically related to endogenous proviruses or to cellular elements. We extended our studies concerning evolutionary conservation and genetic relationships of VL30 sequences within and outside the genus Mus. The following observations were made: (i) Although VL30 DNA sequences were detected in all mice examined, analysis of VL30 reiteration disclosed up to a 100-fold difference among different Mus species. For example, only 1-3 VL30 copies were detected in M. pahari compared to approximately 200 VL30 copies in certain strains of M. musculus. (ii) Using low-stringency hybridization conditions, nucleotide sequences homologous to mouse VL30 DNA were detected in the DNAs of other animal cells such as rat and human. (iii) The cross-hybridization between mouse VL30 DNA and rat genomic DNA was fully accounted for by the cross-homology between the respective VL30 elements. The homologous regions were mapped and were found confined within a small fragment (less than 1kb) in both mouse VL30 and rat 30S DNA (as well as in Ha-MSV). The data suggested differential conservation of subsets of VL30 information. (iv) A subset of VL30 information was found in the mouse genome in molecular linkages other than "standard" VL30 units (that is a segment of VL30 DNA flanked by non-VL30 sequences). Results are discussed in terms of the possible evolution of VL30 sequences.

Animals↗
PubMed2006

Genetic and molecular characterization of CLK-1/mCLK1, a conserved determinant of the rate of aging.

The clk-1 gene of the nematode Caenorhabditis elegans encodes an evolutionarily conserved enzyme that is necessary for ubiquinone biosynthesis. Loss-of-function mutations in clk-1, as well as in its mouse orthologue mclk1, increase lifespan in both organisms. In nematodes, clk-1 extends lifespan by a mechanism that is distinct from the insulin signaling-like pathway but might have similarities to calorie restriction. The evolutionary conservation of the effect of clk-1/mclk1 on lifespan suggests that the gene affects a fundamental mechanism of aging. The clk-1/mclk1 system could allow for the understanding of this mechanism by combining genetic and molecular investigations in worms with studies in mice, where age-dependent disease processes relevant to human health can be modeled.

Aging↗
PubMed1988

The kappa-deleting element. Germline and rearranged, duplicated and dispersed forms.

Human light chain genes are used in a kappa before lambda order. Accompanying this hierarchy is the rearrangement of a kappa-deleting element (Kde) which eliminates the kappa locus before lambda gene rearrangement. In approximately 60% of rearrangements the Kde recombines at a conserved heptamer within the J kappa-C kappa intron. We demonstrated that aberrant V/J rearrangements possessing apparent "N" nucleotides existed 5' to the J kappa-Kde rearrangements. This suggests that the Kde may selectively eliminate nonfunctional V/J alleles. A kappa-producing cell that displayed the unusual finding of lambda gene rearrangement demonstrated a rearranged Kde. This rearrangement was a V kappa/Kde recombination and the heptamer-11 bp spacer-nonamer flanking the V kappa is the target site of the Kde 40% of the time. The mouse possesses a counterpart to the Kde (recombining sequence [RS]) and the highly conserved regions surround the heptamer-spacer-nonamer signals. No complete protein product was predicted from the germline Kde near its break-point and no consistent fusion product was predicted from either the V/Kde or V/J-Kde rearrangements. A distal portion of the Kde is duplicated and is present at 2q11 as well as 2p11. The evolutionary conservation of the kappa-elimination event, the duplication and maintenance of the Kde indicates that it has a function. A portion of the Kde may still prove to encode a trans-acting factor that directly affects lambda rearrangement. A certain role for the Kde is its site-specific rearrangement, which destroys ineffective kappa genes and sets the stage for lambda gene utilization.

Alleles↗
PubMed1988

Conservation and reorganization of loci on the mammalian X chromosome: a molecular framework for the identification of homologous subchromosomal regions in man and mouse.

By means of cross-reacting molecular probes, some 18 loci specific for the X chromosome of both man and mouse have been localized on the mouse X chromosome using an interspecific mouse cross involving the inbred SPE/Pas strain derived from Mus spretus. Comparison of the localizations of these loci on the mouse X with their positions on the human X chromosome suggests that intrachromosomal rearrangements involving at least five X chromosome breakage events must have occurred during the period of evolutionary divergence separating primates from rodents. Within the five blocks of chromosomal material so defined, there is for the moment little or no evidence that either chromosomal inversion events or extensive rearrangements have occurred. These data confirm the remarkable evolutionary conservation of the X chromosome apparent in mammalian species, compared to autosomal synteny groups in which both inter- and intrachromosomal rearrangement events appear to have occurred frequently. The breakage events described here for the X chromosome should therefore provide a minimal estimate for the frequency of chromosomal rearrangement events, such as breakage and inversion, which have affected autosomal synteny groups during the evolutionary period separating man from mouse. The definition of the number of chromosome breakage events by which the X chromosomes of these species differ, together with their localization, provides a framework for the use of interspecies mouse crosses for further detailed mapping of particular subchromosomal regions of the human X chromosome and for defining loci in the mouse homologous to those implicated in human congenital diseases.

Animals↗
PubMed1995

Evolutionarily conserved structural elements are critical for processing of Internal Transcribed Spacer 2 from Saccharomyces cerevisiae precursor ribosomal RNA.

Structural features of Internal Transcribed Spacer 2 (ITS2) important for the correct and efficient removal of this spacer from Saccharomyces cerevisiae pre-rRNA were identified by in vivo mutational analysis based upon phylogenetic comparison with its counterparts from four different yeast species. Compatibility between ITS2 structure and the S. cerevisiae processing machinery was found to have been maintained over only a short evolutionary distance, in contrast to the situation for ITS1. Nevertheless, cis-acting elements required for correct and efficient processing are confined predominantly to those regions of the spacer that show the highest degree of evolutionary conservation. Mutation or deletion of each of these regions severely reduced production of mature 26 S, but not 17 S rRNA, mainly by impeding processing of the 29 SB precursor. In some cases, however, conversion of 29SA into 29 SB pre-rRNA also appeared to be affected. Deletion of non-conserved segments, on the other hand, caused little or no disturbance in processing. Surprisingly, some combinations of such individually neutral deletions had a severe negative effect on the removal of ITS2, suggesting a requirement for a higher-order structure of ITS2. Finally, even structural alterations of ITS2 that did not noticeably affect processing, significantly reduced the growth rate of cells that exclusively express the mutant rDNA units. We take this as further evidence for a direct role of ITS2 in the formation of fully functional 60 S ribosomal subunits.

Base Sequence↗
PubMed2003

Evolutionarily conserved cytoprotection provided by Bax Inhibitor-1 homologs from animals, plants, and yeast.

Programmed cell death (PCD) plays important roles in the development and physiology of both animals and plants, but it is unclear whether similar mechanisms are employed. Bax Inhibitor-1 (BI-1) is an intracellular multi-membrane-spanning protein and cell death inhibitor, originally identified by a function-based screen for mammalian cDNAs capable of suppressing cell death in yeast engineered to ectopically express the pro-apoptotic protein Bax. Using this yeast assay, we screened expression libraries for cDNAs from the plant, Lycopersicon esculentum (tomato), and the invertebrate animal Drosophila melanogaster (fruit fly), identifying close homologs of BI-1 as Bax-suppressors. We studied the fly and tomato homologs of BI-1, as well as BI-1 homologs identified in Arabidopsis thaliana, Oryza sativa (rice), and Saccharomyces cerevisiae (budding yeast). All eukaryotic homologs of BI-1 blocked Bax-induced cell death when expressed in yeast. Eukaryotic BI-1 homologs also partially rescued yeast from cell death induced by oxidative stress (H(2)O(2)) and heat shock. Deletion of a C-terminal domain from BI-1 homologs abrogated their cytoprotective function in yeast, demonstrating conserved structure-function relations among these proteins. Expression of tomato BI-1 by agroinfiltration of intact plant leaves provided protection from damage induced by heat-shock and cold-shock stress. Altogether, these findings indicate that BI-1 homologs exist in multiple eukaryotic species, providing cytoprotection against diverse stimuli, thus implying that BI-1 regulates evolutionary conserved mechanisms of stress resistance that are germane to both plants and animals.

Amino Acid Sequence↗
PubMed1993

The product of the Drosophila melanogaster segment polarity gene armadillo is highly conserved in sequence and expression in the housefly Musca domestica.

Segmental pattern in Drosophila melanogaster is set up via a set of cell-cell interactions mediated by the products of the segment polarity genes. Among these is the armadillo gene, whose product seems to be required for the reception of an intercellular signal encoded by the wingless gene. As part of our effort to relate the structure of the armadillo protein to its function within the cell, we have examined the evolutionary conservation of the armadillo gene during insect evolution. We have cloned the armadillo gene from the housefly, Musca domestica, which diverged from Drosophila 100 million years ago. The Musca protein is 97.5% identical to that in Drosophila, while the noncoding sequences have diverged extensively. This remarkable degree of conservation at the protein level is mirrored in the expression pattern of the armadillo protein. Antibodies against the Drosophila protein cross-react with a Musca protein of the appropriate size. We have also used these antibodies to show that the Musca armadillo protein has a pattern of expression in larval and adult tissues similar to that of Drosophila armadillo. We discuss the implications of conservation of structure and expression for the cellular role of the armadillo protein and its mammalian homologs.

Amino Acid Sequence↗
PubMed1990

Conservation of engrailed-like homeobox sequences during vertebrate evolution.

The Drosophila melanogaster developmental gene engrailed (en) is a member of a distinct subfamily of homeobox genes with a wide phylogenetic distribution. Here we report the use of reduced stringency polymerase chain reaction (PCR) to amplify and clone 8 genes related to en from 5 vertebrate species, including representatives of the most ancient vertebrate lineages. Nucleotide and deduced amino acid sequence comparisons between mouse, toad, zebrafish, lamprey and hagfish genes reveal extensive evolutionary conservation, and suggests that 2 en-like genes have been retained in most vertebrate lineages.

Amino Acid Sequence↗
PubMed1990

Comparative structure and evolution of murine CR2. The homolog of the human C3d/EBV receptor (CD21).

The complete nucleotide sequence of murine complement receptor type 2 (CR2) was determined from two overlapping cDNA clones derived from a lambda gt11 library of late pre-B cell origin. Comparison of the predicted sequence of the 1014 amino acid murine homolog with that of human CR2 revealed marked evolutionary conservation. The murine molecule was 65% identical to human CR2 overall, lacking a single repetitive sequence variably present in man. The 15 approximately 60-75 amino acid short consensus repeats (SCR) that constitute the entire extracellular domain of murine CR2 were 53 to 81% identical to and could be directly aligned with the human protein. As reported, the cytoplasmic tail shared 79% amino acid identity with human CR2, whereas that of the transmembrane was only 33%. Murine CR2 contained 16 potential N-linked glycosylation sites of which 6 were conserved, 4 altered, and 6 lost during human evolution. The hydropathicity profile of the two molecules was nearly colinear with some variation in the N-terminal region of the first repeat, as well as within the sixth and twelfth repeats. RNA blot analysis revealed a approximately 4.0 to 5.0 kb message in murine B lymphocytes, which was absent in T lymphocytes (thymus and spleen), liver, brain, lung, kidney, and heart. A method was devised to more precisely compare the repeat structures. An identity matrix analysis suggests that human ancestral CR2 evolved before divergence of the rodent and primate branches of the evolutionary tree through a series of predictable gene duplications, possibly giving rise to the precursor of human CR1 and murine CRY. The marked structural similarity between the human and murine receptors suggests functional conservation as well.

Amino Acid Sequence↗
PubMed2000

Dissection of functional NF-Y-RFX cooperative interactions on the MHC class II Ea promoter.

Transcription of major histocompatibility complex (MHC) class II genes depends upon the trimeric complexes RFX and NF-Y binding to the conserved X-Y promoter elements. We produced and purified the RFX subunits from Escherichia coli, reconstituted DNA-binding to the mouse Ea X box and dissected the interactions with NF-Y. RFX and NF-Y do not interact in solution, but make cooperative interactions in EMSA: a minimal NF-Y, composed of the evolutionary conserved domains, is sufficient and the RFXAP N-terminal half is expendable. Altering the X-Y distance abolishes cooperativity, indicating that DNA imposes severe spatial constraints. When tested on a highly positioned nucleosome, RFX binds DNA well and NF-Y does not increase its affinity further. Transfections of NF-Y subunits, but not RFX, in class II negative cells improves basal transcription and coexpression of the two activators has a synergistic effect, while modestly increasing CIITA-mediated activation. These results show that interactions between the two trimers on DNA are key to MHC class II expression.

Animals↗
PubMed2002

M13 endopeptidases: New conserved motifs correlated with structure, and simultaneous phylogenetic occurrence of PHEX and the bony fish.

M13 endopeptidase alignments have focused mainly on mammalian sequences and on the active site region defining the catalytic sequence signatures. Aligning all available M13 from bacteria to human on a full-length basis, we have performed a sequence analysis. This enabled us to highlight the origin and function of the M13 PHEX subtype family endopeptidase (phosphate regulating gene with homologies to endopeptidases on the X chromosome). New evolutionary conserved regions in both prokaryotes and eukaryotes have been detected and eukaryotic-specific regions clearly delineated. Using the recently solved neprilysin structure, we have observed that all new motifs, except one, localize in the spatial vicinity of the previously reported catalytic signatures. Interestingly, a highly hydrophobic pocket containing three newly reported motifs is centered by the C-terminal tryptophan residue. Extensive M13 searches in complete and in progress higher eukaryotic genomes have lead to the identification of Danio rerio as the simplest organism having PHEX. Finally, the human PHEX substrate, the parathyroid hormone-related peptide, PTHrP(107-139), is absent in bony fish: this suggests the existence of further PHEX substrates common to both bony fishes and higher vertebrates.

Amino Acid Motifs↗
PubMed1988

Antibodies to the conserved cytoplasmic domain of the integrin beta 1 subunit react with proteins in vertebrates, invertebrates, and fungi.

The integrin family of cell surface receptors can be divided into three groups on the basis of their homologous beta subunits: beta 1, beta 2, and beta 3. We have raised an antibody against a synthetic peptide corresponding to the COOH-terminal domain of the chicken integrin beta 1 subunit that reacts with beta subunits from a variety of vertebrates, invertebrates, and fungi, demonstrating strong evolutionary conservation of sequences in this domain. In Drosophila cells, the antibody recognizes integrin alpha beta complexes that appear to be identical with position-specific antigens. Cross-reactive proteins are also detected in Caenorhabditis elegans and Candida albicans. The antiserum is specific for beta 1 subunits and does not recognize other integrin beta subunits in humans. In immunofluorescence analyses of cultured cells, the antibody reacts only with permeabilized cells confirming that this highly conserved COOH-terminal segment is a cytoplasmic domain.

Amino Acid Sequence↗
PubMed1999

Conservation of neurogenic genes and mechanisms.

Reports from the past year have demonstrated that neural basic helix-loop-helix genes and LIM homeobox genes contribute to neuronal subtype specification in vertebrates and invertebrates, that Notch signaling specifies cell fates in the developing vertebrate inner ear, and that the organization of the central nervous system into three columns is shared by vertebrates and invertebrates. These findings pave the way for future work that will help to establish the extent to which these similarities represent evolutionary conservation.

Animals↗
PubMed1997

A novel protein with strong homology to the tumor suppressor p53.

The p53 tumor suppressor orchestrates a number of important genes involved in cell-cycle control and apoptosis. Mice deficient for p53 show a high incidence of cancer but are developmentally normal suggesting that compensatory mechanisms exist in embryogenesis and differentiation. The new KET protein is the first mammalian protein with strong homology to p53 in all evolutionary conserved regions. This conservation makes a functional redundancy of the two proteins in cell-cycle control possible. KET is expressed during embryonic development and in certain adult tissues. Among all of the known p53 proteins of different species KET is most closely related to that found in squid. The relationship between KET and the invertebrate p53 protein sheds light on the evolutionary origin of p53. KET appears to be an ancestral p53-related protein in vertebrates with a possible role in development and differentiation while the ubiquitously expressed p53 protein attained its general role as 'guardian of the genome' during evolution.

Amino Acid Sequence↗