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PubMed2006

Teneurin C-terminal associated peptides: an enigmatic family of neuropeptides with structural similarity to the corticotropin-releasing factor and calcitonin families of peptides.

The proliferation of genomic sequence data in recent years has led to the identification of numerous orthologous and paralogous genes in a variety of divergent taxa. Phylogenetic comparisons of this sequence information have led not only to the construction of improved evolutionary relationships among genes and species, but also led to greater understanding of how genes and their proteins evolve differently throughout the Metazoa. Our recent characterization of a biologically active corticotropin-releasing factor (CRF)-like sequence at the C-terminal region of the teneurin transmembrane proteins has led to a number of questions of how peptide genes evolve and develop new functions in the Metazoa. The teneurin C-terminal associated peptides show structural similarity to the calcitonin family of peptides as well as the CRF family, and like both peptide families, plays a role in the regulation of stress and anxiety.

Amino Acid Sequence↗
PubMed2004

Characterization of the human STAT5A and STAT5B promoters: evidence of a positive and negative mechanism of transcriptional regulation.

We recently published the genomic characterization of the STAT5A and STAT5B paralogous genes that are located head to head in the 17q21 chromosome and share large regions of sequence identity. We here demonstrate by transient in vitro transfection that STAT5A and STAT5B promoters are able to direct comparable levels of transcription. The expression of basal promoters is enhanced after Sp1 up-regulation in HeLa and SL2 cells while DNA methylation associated to the recruitment of MeCP2 methyl CpG binding protein down-regulates STAT5A and B promoters by interfering with Sp1-induced transcription. In addition, cross-species sequence comparison identified a bi-directional negative cis-acting regulatory element located in the STAT5 intergenic region.

Animals↗
PubMed1999

The Sp-family of transcription factors.

GC-boxes and related motifs are frequently occurring DNA-elements present in many promoters and enhancers. In contrast to other elements it was generally thought that the transcription factor Sp1 is the only factor acting through these motifs. The cloning of paralogous genes of the Sp1 factor uncovered the existence of a small protein family consisting of Sp1, Sp2, Sp3 and Sp4. All four proteins exhibit very similar structural features. They contain a highly conserved DNA-binding domain composed of three zinc fingers close the C-terminus and serine/threonine- and glutamine-rich domains in their N-terminal regions. The high degree of structural conservation between these four proteins suggested that they do exert similar functions. Molecular, genetic and biochemical analyses, however, demonstrated that Sp2, Sp3 and Sp4 are not simply functional equivalents of Sp1. Here, I will summarize and discuss recent advances which have been made towards understanding the mode of action and biological function of individual family members.

Amino Acid Sequence↗
PubMed1998

Analysis of Hoxa7/Hoxb7 mutants suggests periodicity in the generation of the different sets of vertebrae.

Mice were generated with targeted disruptions in Hoxa7 and Hoxb7, respectively. Mice carrying the Hoxa7 mutation are healthy. No abnormalities in the formation of the skeleton or other tissues were found in these mutants. Twelve percent of Hoxb7-/- mutants show first and second rib defects similar to those observed in mice homozygous for a Hoxb9 mutation (Chen, F., Capecchi, M.R., 1997. Dev. Biol. 181, 186-196). Hoxb7-/- mice are also fertile and were used to generate double mutants with Hoxa7 to reveal potential interactions between these two paralogous genes. Mice homozygous for both mutations have first and second rib defects with higher penetrance and increased expressivity, indicating a functional role for Hoxa7 in the patterning of the upper thoracic region. Although Hoxb6, Hoxa7, Hoxb7, and Hoxb9 have distinctive anterior expression limits in axial mesoderm, the disruptions of these genes all yield first and second rib defects. A hypothesis is suggested to explain the observation that axial defects in these and other mouse Hox mutants appear to concentrate along the axial column at zones of transition between vertebral types.

Animals↗
PubMed2005

Enzymatic hydrogenation of trans-2-nonenal in barley.

Conversion of undesirable, taste-active compounds is crucial for using barley as a suitable raw material for beer production. Here, ALH1, a barley alkenal hydrogenase enzyme that reduced the alpha,beta-unsaturated double bond of aldehydes and ketones, was found to convert trans-2-nonenal (T2N), a major contributor to the cardboard-like flavor of aged beer. Although the physiological function of ALH1 in barley development remains elusive, it exhibited high specificity with NADPH as a cofactor in the conversion of several oxylipins-including T2N, trans-2-hexenal, traumatin, and 1-octen-3-one. ALH1 action represents a previously unknown mechanism for T2N conversion in barley. Additional experimental results resolved the genomic sequence for barley ALH1, as well as the identification of a paralog gene encoding ALH2. Interestingly, T2N was not converted by purified, recombinant ALH2. The possibility to enhance ALH1 activity in planta is discussed--not only with respect to the physiological consequences thereof--but also in relation to improved beer quality.

Aldehydes↗
PubMed2007

Trafficking of phosphatidylinositol by phosphatidylinositol transfer proteins.

PtdIns is synthesized at the endoplasmic reticulum and its intracellular distribution to other organelles can be facilitated by lipid transfer proteins [PITPs (phosphatidylinositol transfer proteins)]. In this review, I summarize the current understanding of how PITPs are regulated by phosphorylation, how can they dock to membranes to exchange their lipid cargo and how cells use PITPs in signal transduction and membrane delivery. Mammalian PITPs, PITPalpha and PITPbeta, are paralogous genes that are 94% similar in sequence. Their structural design demonstrates that they can sequester PtdIns or PtdCho (phosphatidylcholine) in their hydrophobic cavity. To deliver the lipid cargo to a membrane, PITP has to undergo a conformational change at the membrane interface. PITPs have a higher affinity for PtdIns than PtdCho, which is explained by hydrogen-bond contacts between the inositol ring of PtdIns and the side-chains of four amino acid residues, Thr59, Lys61, Glu86 and Asn90, in PITPs. Regardless of species, these residues are conserved in all known PITPs. PITP transfer activity is regulated by a conserved serine residue (Ser166) that is phosphorylated by protein kinase C. Ser166 is only accessible for phosphorylation when a conformational change occurs in PITPs while docking at the membrane interface during lipid transfer, thereby coupling regulation of activity with lipid transfer function. Biological roles of PITPs include their ability to couple phospholipase C signalling to neurite outgrowth, cell division and stem cell growth.

Animals↗
PubMed2002

FEEL-1, a novel scavenger receptor with in vitro bacteria-binding and angiogenesis-modulating activities.

Employing the expression cloning technique, we cloned a novel scavenger receptor that is structurally unrelated to other scavenger receptors. The cloned receptor contained fasciclin (Fas-1), epidermal growth factor (EGF)-like, laminin-type EGF-like, and link domains. Based on the domain structures, we temporarily named it FEEL-1 (fasciclin, EGF-like, laminin-type EGF-like, and link domain-containing scavenger receptor-1). A data base search suggested the presence of a paralogous gene of FEEL-1, the full-length cDNA of this gene was also cloned, and its nucleotide sequence was determined. The deduced amino acid sequence of the clone indicated that its domain organization is similar to FEEL-1, and we named this clone FEEL-2. The effect of monoclonal antibodies against FEEL-1 indicated that FEEL-1 is the major receptor for 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbo-cyanine perchlorate (DiI)-labeled acetylated low density lipoprotein (DiI-Ac-LDL) in human umbilical vein endothelial cells. Reverse transcription and PCR analysis revealed that both FEEL-1 and FEEL-2 were expressed in several tissues and expressed highly in the spleen and lymph node. On the other hand, only FEEL-1 was expressed in mononuclear cells, particularly resting CD14(+) cells. The transient expression of FEEL-1 and FEEL-2 in Chinese hamster ovary cells demonstrated that both FEELs could bind to DiI-Ac-LDL. Both receptors were also found to bind to Gram-negative and Gram-positive bacteria. These results suggest that FEELs play important roles in the defense mechanisms against bacterial infection. Finally, the phenotypic effect of the inhibition of FEEL-1 on vascular remodeling was tested in vitro using the Matrigel tube formation assay, and we found a marked reduction in the degree of cell-cell interaction in anti-FEEL-1 monoclonal antibody-treated cells, suggesting the role of this receptor in angiogenesis.

Amino Acid Sequence↗
PubMed2004

Roles of conserved proline and glycosyltransferase motifs of EmbC in biosynthesis of lipoarabinomannan.

D-Arabinans, composed of D-arabinofuranose (D-Araf), dominate the structure of mycobacterial cell walls in two settings, as part of lipoarabinomannan (LAM) and arabinogalactan, each with markedly different structures and functions. Little is known of the complexity of their biosynthesis. beta-D-Arabinofuranosyl-1-monophosphoryldecaprenol is the only known sugar donor. EmbA, EmbB, and EmbC, products of the paralogous genes embA, embB, and embC, the sites of resistance to the anti-tuberculosis drug ethambutol (EMB), are the only known implicated enzymes. EmbA and -B apparently contribute to the synthesis of arabinogalactan, whereas EmbC is reserved for the synthesis of LAM. The Emb proteins show no overall similarity to any known proteins beyond Mycobacterium and related genera. However, functional motifs, equivalent to a proline-rich motif of several bacterial polysaccharide co-polymerases and a superfamily of glycosyltransferases, were found. Site-directed mutagenesis in glycosyltransferase superfamily C resulted in complete ablation of LAM synthesis. Point mutations in three amino acids of the proline motif of EmbC resulted in marked reduction of LAM-arabinan synthesis and accumulation of an unknown intermediate and of the known precursor lipomannan. Yet the pattern of the differently linked d-Araf units observed in wild type LAM-arabinan was largely retained in the proline motif mutants. The results allow for the presentation of a unique model of arabinan synthesis.

Amino Acid Motifs↗
PubMed2006

A chromosomal rearrangement hotspot can be identified from population genetic variation and is coincident with a hotspot for allelic recombination.

Insights into the origins of structural variation and the mutational mechanisms underlying genomic disorders would be greatly improved by a genomewide map of hotspots of nonallelic homologous recombination (NAHR). Moreover, our understanding of sequence variation within the duplicated sequences that are substrates for NAHR lags far behind that of sequence variation within the single-copy portion of the genome. Perhaps the best-characterized NAHR hotspot lies within the 24-kb-long Charcot-Marie-Tooth disease type 1A (CMT1A)-repeats (REPs) that sponsor deletions and duplications that cause peripheral neuropathies. We investigated structural and sequence diversity within the CMT1A-REPs, both within and between species. We discovered a high frequency of retroelement insertions, accelerated sequence evolution after duplication, extensive paralogous gene conversion, and a greater than twofold enrichment of SNPs in humans relative to the genome average. We identified an allelic recombination hotspot underlying the known NAHR hotspot, which suggests that the two processes are intimately related. Finally, we used our data to develop a novel method for inferring the location of an NAHR hotspot from sequence variation within segmental duplications and applied it to identify a putative NAHR hotspot within the LCR22 repeats that sponsor velocardiofacial syndrome deletions. We propose that a large-scale project to map sequence variation within segmental duplications would reveal a wealth of novel chromosomal-rearrangement hotspots.

Alleles↗
PubMed2005

Modeling genome evolution with a diffusion approximation of a birth-and-death process.

MOTIVATION: In our previous studies, we developed discrete-space birth, death and innovation models (BDIMs) of genome evolution. These models explain the origin of the characteristic Pareto distribution of paralogous gene family sizes in genomes, and model parameters that provide for the evolution of these distributions within a realistic time frame have been identified. However, extracting the temporal dynamics of genome evolution from discrete-space BDIM was not technically feasible. We were interested in obtaining dynamic portraits of the genome evolution process by developing a diffusion approximation of BDIM. RESULTS: The diffusion version of BDIM belongs to a class of continuous-state models whose dynamics is described by the Fokker-Plank equation and the stationary solution could be any specified Pareto function. The diffusion models have time-dependent solutions of a special kind, namely, generalized self-similar solutions, which describe the transition from one stationary distribution of the system to another; this provides for the possibility of examining the temporal dynamics of genome evolution. Analysis of the generalized self-similar solutions of the diffusion BDIM reveals a biphasic curve of genome growth in which the initial, relatively short, self-accelerating phase is followed by a prolonged phase of slow deceleration. This evolutionary dynamics was observed both when genome growth started from zero and proceeded via innovation (a potential model of primordial evolution), and when evolution proceeded from one stationary state to another. In biological terms, this regime of evolution can be tentatively interpreted as a punctuated-equilibrium-like phenomenon whereby evolutionary transitions are accompanied by rapid gene amplification and innovation, followed by slow relaxation to a new stationary state.

Algorithms↗
PubMed2005

Mouse Siglec-F and human Siglec-8 are functionally convergent paralogs that are selectively expressed on eosinophils and recognize 6'-sulfo-sialyl Lewis X as a preferred glycan ligand.

Mouse sialic acid-binding immunoglobulin-like lectin F (Siglec-F) is an eosinophil surface receptor, which contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain, implicating it as a regulator of cell signaling as documented for other siglecs. Here, we show that the sialoside sequence 6'-sulfo-sLe(X) (Neu5Acalpha2-3[6-SO4] Galbeta1-4[Fucalpha1-3]GlcNAc) is a preferred ligand for Siglec-F. In glycan array analysis of 172 glycans, recombinant Siglec-F-Fc chimeras bound with the highest avidity to 6'-sulfo-sLe X. Secondary analysis showed that related structures, sialyl-Lewis X (sLe X) and 6-sulfo-sLe X containing 6-GlcNAc-SO4 showed much lower binding avidity, indicating significant contribution of 6-Gal-SO4 on Siglec-F binding to 6'-sulfo-sLe x. The lectin activity of Siglec-F on mouse eosinophils was "masked" by endogenous cis ligands and could be unmasked by treatment with sialidase. Unmasked Siglec-F mediated mouse eosinophil binding and adhesion to multivalent 6'-sulfo-sLe X structure, and these interactions were inhibited by anti-Siglec-F monoclonal antibody (mAb). Although there is no clear-cut human ortholog of Siglec-F, Siglec-8 is encoded by a paralogous gene that is expressed selectively by human eosinophils and has recently been found to recognize 6'-sulfo-sLe X. These observations suggest that mouse Siglec-F and human Siglec-8 have undergone functional convergence during evolution and implicate a role for the interaction of these siglecs with their preferred 6'-sulfo-sLe X ligand in eosinophil biology.

Animals↗
PubMed2004

Human SCO1 and SCO2 have independent, cooperative functions in copper delivery to cytochrome c oxidase.

Human SCO1 and SCO2 are paralogous genes that code for metallochaperone proteins with essential, but poorly understood, roles in copper delivery to cytochrome c oxidase (COX). Mutations in these genes produce tissue-specific COX deficiencies associated with distinct clinical phenotypes, although both are ubiquitously expressed. To investigate the molecular function of the SCO proteins, we characterized the mitochondrial copper delivery pathway in SCO1 and SCO2 patient backgrounds. Immunoblot analysis of patient cell lines showed reduced levels of the mutant proteins, resulting in a defect in COX assembly, and the appearance of a common assembly intermediate. Overexpression of the metallochaperone COX17 rescued the COX deficiency in SCO2 patient cells but not in SCO1 patient cells. Overexpression of either wild-type SCO protein in the reciprocal patient background resulted in a dominant-negative phenotype, suggesting a physical interaction between SCO1 and SCO2. Chimeric proteins, constructed from the C-terminal copper-binding and N-terminal matrix domains of the two SCO proteins failed to complement the COX deficiency in either patient background, but mapped the dominant-negative phenotype in the SCO2 background to the N-terminal domain of SCO1, the most divergent part of the two SCO proteins. Our results demonstrate that the human SCO proteins have non-overlapping, cooperative functions in mitochondrial copper delivery. Size exclusion chromatography suggests that both the proteins function as homodimers. We propose a model in which COX17 delivers copper to SCO2, which in turn transfers it directly to the CuA site at an early stage of COX assembly in a reaction that is facilitated by SCO1.

Biological Transport↗
PubMed2003

The Drosophila melanogaster BTB proteins bric à brac bind DNA through a composite DNA binding domain containing a pipsqueak and an AT-Hook motif.

The bric à brac (bab) locus is composed of two paralogous genes, bab1 and bab2, in Drosophila melanogaster. Bab1 and Bab2 are nuclear proteins that contain a broad complex, tramtrack, bric à brac/poxviruses and zinc-finger (BTB/POZ) domain. Many BTB/POZ proteins are transcriptional regulators of which the majority contain C(2)H(2) zinc-finger motifs. There is no detectable zinc-finger motif in either Bab protein. However, they share the Bab conserved domain (BabCD) that is highly conserved between Bab1 and Bab2, and the Bab proteins of several other species, e.g. Anopheles gambiae, Apis mellifera and Drosophila virilis. Here we show that Bab2 binds to several discrete sites on polytene chromosomes including the bab locus, and that the BabCD of both Bab1 and Bab2 binds in vitro to the cis-regulatory regions of bab1 and bab2. Our results indicate that the BabCD binds to A/T-rich regions and that its optimum binding sites contain TA or TAA repeats. The BabCD is a composite DNA binding domain with a psq motif and an AT-Hook motif; both motifs are required for DNA binding activity. Structural similarities suggest that the BabCD may bind to DNA in a similar manner as some prokaryotic recombinases.

Amino Acid Sequence↗
PubMed2002

Evolution of hematophagy in ticks: common origins for blood coagulation and platelet aggregation inhibitors from soft ticks of the genus Ornithodoros.

Identification and characterization of antihemostatic components from hematophagous organisms are useful for the elucidation of the evolutionary mechanisms involved in adaptation to a highly complex host hemostatic system. Although many bioactive components involved in the regulation of the host's hemostatic system have been described, the evolutionary mechanisms of how arthropods adapted to a blood-feeding environment have not been elucidated. This study describes common origins of both blood coagulation inhibitors and platelet aggregation inhibitors (PAIs) from soft ticks of the genus Ornithodoros. Neighbor-joining analysis indicates that fXa, thrombin, and PAIs share a common ancestor. Maximum parsimony analysis and a phylogeny based on root mean square deviation values of alpha-carbon backbone structures suggest a novel evolutionary pathway by which different antihemostatic functions have evolved through a series of paralogous gene duplication events. In this scenario, the thrombin inhibitors preceded the fXa and PAIs. This evolutionary model explains why the tick serine protease inhibitors have inhibition mechanisms that differ from that of the canonical bovine pancreatic trypsin inhibitor (BPTI)-like inhibitors. Higher nonsynonymous-to-synonymous substitution rates indicate positive Darwinian selection for the fXa and PAIs. Comparison with hemostatic inhibitors of hard ticks suggests that the two main tick families have independently evolved novel antihemostatic mechanisms. Independent evolution of these mechanisms in ticks points to a rapid divergence between tick families that could be dated between 120 and 92 MYA. This coincides with current molecular phylogeny views on the early divergence of modern birds and placental mammals in the Late Cretaceous, which suggests that this event might have been a driving force in the evolution of hematophagy in ticks.

Amino Acid Sequence↗
PubMed1995

Phylogenetic analysis of the 90 kD heat shock family of protein sequences and an examination of the relationship among animals, plants, and fungi species.

The heat shock protein (Hsp) sequences, because of their ubiquity and high degree of conservation, provide useful models for phylogenetic analysis. In this paper I have carried out a global alignment of all available sequences (a total of 31) for the 90-kD heat shock protein (Hsp90) family. The minimum amino acid identity that is seen between presently known Hsp90 homologs is about 40% over the entire length, indicating that it is a highly conserved protein. Based on the alignment, a number of signature sequences that either are distinctive of the Hsp90 family or that distinguish between the cytosolic and the endoplasmic reticular forms of Hsp90 have been identified. Detailed phylogenetic analyses based on Hsp90 sequences reported here strongly indicate that the cytosolic and the endoplasmic reticulum (ER) resident forms of Hsp90 constitute paralogous gene families which arose by a gene duplication event that took place very early in the evolution of eukaryotic cells. A minimum of two additional gene duplication events, which took place at a later time, are required to explain the presence of two different forms of Hsp90 that are found in fungi and vertebrate species. In a consensus neighbor-joining bootstrap tree based on Hsp90 sequences, plants and animals species grouped together 989 times of 1,000 (a highly significant score), indicating a closer relationship between them as compared to fungi. A closer affiliation of plant and animal species was also observed in the maximum-parsimony tree, although the relationship was not significantly supported by this method. A survey of the recent literature on this subject indicates that depending on the protein sequence and the methods of phylogenetic analysis, the animal species are indicated as closer relatives to either plants or fungi with significant statistical support for both topologies. Thus the relationship among the animal, plant, and fungi kingdoms remains an unresolved issue at the present time.

Amino Acid Sequence↗
PubMed1987

The evolution of prokaryotic ferredoxins--with a general method correcting for unobserved substitutions in less branched lineages.

Thirty-one bacterial type ferredoxins were examined by means of the parsimony method for their phylogenetic implications. The results show reasonable relationships in that photosynthetic, thermophilic, and desulfovibrio groups are identifiable; but a number of interesting anomalies occur. These include a methanogen sequence that clusters among the desulfovibrios. There are several differences from the phylogeny of Woese. At least two duplications producing paralogous genes are demonstrated, plus the probable existence of two more. The partial internal gene duplication that doubled the length of ferredoxin is confirmed by showing that the probability of the two ancestrally reconstructed halves possessing that much similarity by chance is 10(-7). Howard and co-workers proposed that the two halves of the Azotobacter vinelandii are reversed relative to most other sequences. A phylogeny, drawn with the halves of the azotobacter sequence (and its relatives) reversed produced a tree that had only three less nucleotide substitutions than did the tree without their halves reversed. This plus other evidence suggests that the significantly greater similarity observed across rather than within the halves is more likely the result of convergence.

Amino Acid Sequence↗
PubMed2002

Developmental control of promoter activity is not responsible for mature onset of Cf-9B-mediated resistance to leaf mold in tomato.

Cf-9 confers resistance to tomato seedlings and mature plants against Cladosporium fulvum races expressing the Avr9 elicitor. It is the central member of a cluster of five paralogous genes in an introgressed segment of chromosome 1 derived from Lycopersicon pimpinellifolium. The other four genes have been named Hcr9-9A, Hcr9-9B, Hcr9-9D, and Hcr9-9E. Hcr9-9B, here designated Cf-9B, encodes weaker resistance than Cf-9, recognizes a different elicitor, and protects only mature plants from infection. The onset of Cf-9B-mediated resistance and the molecular basis for its developmental control were investigated in this study. Fungal inoculation of tomato plants containing reciprocal Cf-9/Cf-9B promoter-coding region swaps, analysis of tomato plants containing promoter-gusA fusions, and a reverse transcriptase-polymerase chain reaction study of Cf-9 and Cf-9B transcripts in tomato plants suggested that transcriptional control of Cf-9B did not account for the late onset of Cf-9B-mediated resistance. Alternative explanations for the onset of Cf-9B-mediated resistance in mature plants are discussed.

Base Sequence↗
PubMed2003

Immunological and genetic characterization of Borrelia burgdorferi BapA and EppA proteins.

A large majority of examined Lyme disease spirochaete isolates were demonstrated to contain one or both of the paralogous genes bapA and eppA. Immunological analyses of serum samples collected from infected patients coupled with comparative sequence analyses indicated that bapA gene sequences are quite stable but the encoded proteins do not provoke a strong immune response in most individuals. Conversely, EppA proteins are much more antigenic but vary widely in sequence between different bacteria. Considerable evidence of insertion, deletion and other mutations within eppA genes was observed. A number of significant recombination events were also found to have occurred in regions flanking bapA genes, while the genes themselves rarely exhibited evidence of mutation, suggesting strong selective pressure to maintain BapA sequences within narrow limits. Data from these and other studies suggest important roles for BapA and EppA during the Borrelia burgdorferi infectious cycle.

Amino Acid Sequence↗