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PubMed2006

The NH2-terminal php domain of the alpha subunit of the Escherichia coli replicase binds the epsilon proofreading subunit.

The alpha subunit of the replicase of all bacteria contains a php domain, initially identified by its similarity to histidinol phosphatase but of otherwise unknown function (Aravind, L., and Koonin, E. V. (1998) Nucleic Acids Res. 26, 3746-3752). Deletion of 60 residues from the NH2 terminus of the alpha php domain destroys epsilon binding. The minimal 255-residue php domain, estimated by sequence alignment with homolog YcdX, is insufficient for epsilon binding. However, a 320-residue segment including sequences that immediately precede the polymerase domain binds epsilon with the same affinity as the 1160-residue full-length alpha subunit. A subset of mutations of a conserved acidic residue (Asp43 in Escherichia coli alpha) present in the php domain of all bacterial replicases resulted in defects in epsilon binding. Using sequence alignments, we show that the prototypical gram+ Pol C, which contains the polymerase and proofreading activities within the same polypeptide chain, has an epsilon-like sequence inserted in a surface loop near the center of the homologous YcdX protein. These findings suggest that the php domain serves as a platform to enable coordination of proofreading and polymerase activities during chromosomal replication.

Amino Acid Sequence↗

PubMed1995

Insulin and epidermal growth factor receptors contain the cysteine repeat motif found in the tumor necrosis factor receptor.

The insulin receptor (INSR) and epidermal growth factor receptor (EGFR) are representatives of two structurally related subfamilies of tyrosine kinase receptors. Using the Wisconsin GCG sequence analysis programs, we have demonstrated that the cysteine-rich regions of INSR and EGFR conform to the structural motif found in the tumor necrosis factor receptor (TNFR) family. The study also revealed that these regions were not composed of simple repeats of eight cysteine residues as previously proposed and that the second Cys-rich region of EGFR contained one fewer TNFR repeat than the first. The sequence alignments identified two cysteine residues in INSR that could be responsible for the additional disulfide bonds known to be involved in dimer formation. The published data on the alignments for the fibronectin type III repeat region of the INSR together with previous cysteine mutagenesis studies indicated that there were two disulfide bonds linking the alpha and beta chains of the INSR, but only one alpha-beta linkage in the insulin-like growth factor 1 receptor (IG1R). Database searches and sequence alignments showed that the TNFR motif is also found in the cysteine-rich repeats of laminins and the noncatalytic domains of furin-like proteases. If the starting position of the repeat is altered the characteristic laminin repeat of eight cysteine residues can be shown to consist of a TNFR-like motif fused to the last half of an EGF-like repeat. The overlapping regions of these two motifs are known to have identical disulfide bonding patterns and similar protein folds.

Amino Acid Sequence↗

PubMed2006

SeqVis: visualization of compositional heterogeneity in large alignments of nucleotides.

UNLABELLED: Most phylogenetic methods assume that the sequences evolved under homogeneous, stationary and reversible conditions. Compositional heterogeneity in data intended for studies of phylogeny suggests that the data did not evolve under these conditions. SeqVis, a Java application for analysis of nucleotide content, reads sequence alignments in several formats and plots the nucleotide content in a tetrahedron. Once plotted, outliers can be identified, thus allowing for decisions on the applicability of the data for phylogenetic analysis. AVAILABILITY: http://www.bio.usyd.edu.au/jermiin/programs.htm.

Algorithms↗

PubMed1999

Protein folds and families: sequence and structure alignments.

Dali and HSSP are derived databases organizing protein space in the structurally known regions. We use an automatic structure alignment program (Dali) for the classification of all known 3D structures based on all-against-all comparison of 3D structures in the Protein Data Bank. The HSSP database associates 1D sequences with known 3D structures using a position-weighted dynamic programming method for sequence profile alignment (MaxHom). As a result, the HSSP database not only provides aligned sequence families, but also implies secondary and tertiary structures covering 36% of all sequences in Swiss-Prot. The structure classification by Dali and the sequence families in HSSP can be browsed jointly from a web interface providing a rich network of links between neighbours in fold space, between domains and proteins, and between structures and sequences. In particular, this results in a database of explicit multiple alignments of protein families in the twilight zone of sequence similarity. The organization of protein structures and families provides a map of the currently known regions of the protein universe that is useful for the analysis of folding principles, for the evolutionary unification of protein families and for maximizing the information return from experimental structure determination. The databases are available from http://www.embl-ebi.ac.uk/dali/

Databases, Factual↗

PubMed1981

On cytochrome c3 folding.

The structure of cytochrome c3 from Desulfovibrio vulgaris Miyazaki (DvM) is considered in detail by scrutinizing main chain folding together with the structure of the protein from D. desulfuricans Norway (DdN). The relative arrangement of the four heme groups in this molecule is similar to that of DdN and the disposition of alpha-carbon atoms of cysteine and histidine residues binding to heme groups is also similar. Structural differences between the two proteins occur in the shape of some specific loops of the chain on the molecular surface. As a result of a careful comparison of structures and sequences in both cytochromes c3, the reported sequence alignment of the cytochrome c3 family has been revised. Our new proposal of a sequence alignment based on the three-dimensional structures contains 24 evolutionarily conservative residues. All these conservative residues may play an important role in the folding pattern of cytochromes c3.

Amino Acid Sequence↗

PubMed1999

Database of biologically active peptide sequences.

Proteins are sources of many peptides with diverse biological activity. Such peptides are considered as valuable components of foods with desired and designed biological activity. Two strategies are currently recommended for research in the area of biological activity of food protein fragments. The first strategy covers investigations on products of enzymic hydrolysis of proteins. The second one is synthesis of peptides identical with protein fragments and investigations using these peptides. It is possible to predict biological activity of protein fragments using sequence alignments between proteins and biologically active peptides from database. Our database contains currently 527 sequences of bioactive peptides with antihypertensive, opioid, immunomodulating and other activities. The sequence alignments can give information about localization of biologically active fragments in protein chain, but not about possibilities of enzymic release of such fragments. The information is thus equivalent with this obtained using synthetic peptides identical with protein fragments. Possibilities offered by the database are discussed using wheat alpha/beta-gliadin, bovine beta-lactoglobulin and bovine beta-casein (including influence of genetic polymorphism and genetic engineering on amino acid sequences) as examples.

Animals↗

PubMed1993

A rat brain cDNA encoding the neurotransmitter transporter with an unusual structure.

A rat cDNA clone encoding the novel membrane protein of the neurotransmitter transporters family was cloned and sequenced. The cDNA was identified as a transcript of the gene NTT4 of which a partial genomic clone was previously sequenced. Alignment of the amino acid sequence of NTT4 with other members of the neurotransmitter transporter family revealed a marked deviation from the conserved structure of all other members of the family. The largest extracellular loop with a potential glycosylation site was identified between membrane segments 7 and 8. The protein retains the common glycosylated loop between transmembrane helices 3 and 4 in all members of the family. The transcript of NTT4 was found exclusively in the central nervous system and is more abundant in the cerebellum and the cerebral cortex.

Amino Acid Sequence↗

PubMed1998

Use of a neural network secondary structure prediction to define targets for mutagenesis of herpes simplex virus glycoprotein B.

Herpes simplex virus glycoprotein B (HSV gB) is essential for penetration of virus into cells, for cell-to-cell spread of virus, and for cell-cell fusion. Every member of the family Herpesviridae has a gB homolog, underlining its importance. The antigenic structure of gB has been studied extensively, but little is known about which regions of the protein are important for its roles in virus entry and spread. In contrast to successes with other HSV glycoproteins, attempts to map functional domains of gB by insertion mutagenesis have been largely frustrated by the misfolding of most mutants. The present study shows that this problem can be overcome by targeting mutations to the loop regions that connect alpha-helices and beta-strands, avoiding the helices and strands themselves. The positions of loops in the primary sequence were predicted by the PHD neural network procedure, using a multiple sequence alignment of 19 alphaherpesvirus gB sequences as input. Comparison of the prediction with a panel of insertion mutants showed that all mutants with insertions in predicted alpha-helices or beta-strands failed to fold correctly and consequently had no activity in virus entry; in contrast, half the mutants with insertions in predicted loops were able to fold correctly. There are 27 predicted loops of four or more residues in gB; targeting of mutations to these regions will minimize the number of misfolded mutants and maximize the likelihood of identifying functional domains of the protein.

Amino Acid Sequence↗

PubMed2003

ITS probe development for specific detection of Rhizoctonia spp. and Suillus bovinus based on Southern blot and liquid hybridization-fragment length polymorphism.

Development of specific DNA probes targeting rDNA internal transcribed spacer (ITS-1 or -2) sequences is described for the detection of strains representing uninucleate and binucleate Rhizoctonia spp. and Suillus bovinus. Discriminatory taxon/species-specific target sequences were identified following full length ITS sequence alignment of the test fungal sequences and those of other root associated pathogenic or mycorrhizal fungi. Both long (124-151 bp) and shorter (20-25 bp) probes were generated for assessment in Southern dot blot and liquid hybridization ITS capture-fragment length polymorphism assays. Fungal genomic DNA was presented as the target in dot blot protocols using the longer DIG (digoxigenin) labelled probes whilst the shorter 3' biotin-labelled oligonucleotide probes were hybridized to PCR amplified full length ITS (ITS1-5.8S-ITS2) in both dot blot and liquid hybridization assays. The optimal hybridization temperatures for dot blot detection also produced maximal target specific signals in the liquid hybridization protocol. The latter protocol was found to be more discriminatory as target fungi were detected on the basis of combined probe hybridization-ITS capture and 5' Cy-5 labelled ITS length polymorphism analysis (+/- 5 bp) following denaturing sequencing gel electrophoresis in a ALFexpress DNA sequencer.

Base Sequence↗

PubMed2005

Natural-like function in artificial WW domains.

Protein sequences evolve through random mutagenesis with selection for optimal fitness. Cooperative folding into a stable tertiary structure is one aspect of fitness, but evolutionary selection ultimately operates on function, not on structure. In the accompanying paper, we proposed a model for the evolutionary constraint on a small protein interaction module (the WW domain) through application of the SCA, a statistical analysis of multiple sequence alignments. Construction of artificial protein sequences directed only by the SCA showed that the information extracted by this analysis is sufficient to engineer the WW fold at atomic resolution. Here, we demonstrate that these artificial WW sequences function like their natural counterparts, showing class-specific recognition of proline-containing target peptides. Consistent with SCA predictions, a distributed network of residues mediates functional specificity in WW domains. The ability to recapitulate natural-like function in designed sequences shows that a relatively small quantity of sequence information is sufficient to specify the global energetics of amino acid interactions.

Amino Acid Sequence↗

PubMed2003

Relationship between the DNA binding domains of SMAD and NFI/CTF transcription factors defines a new superfamily of genes.

Transcription factors of the SMAD family relay signals from cell surface receptors to the nucleus in response to TGF-beta related soluble factors. Members of the nuclear factor I/CAAT box binding family (NFI/CTF) have been implicated as regulators of diverse biological processes such as adenovirus replication and transcription of TGF-responsive genes. There are highly conserved DNA binding domains in SMAD and NFI/CTF transcription factors that allow sequence specific DNA binding for members of each family. However, no homology relationship has been established for the DNA binding domains present in these families. For a better understanding of the structure and evolution of SMAD genes, we carried out a sensitive PSI-BLAST database search. This revealed significant similarities between the DNA binding domains of SMADs and NFI/CTF transcription factors. Enhanced graphic matrix analysis and multiple sequence alignment of the amino acid sequences of the SMAD and NFI/CTF DNA binding domains also show that these two classes of domains share considerable structural similarity. These results strongly suggest that these two classes of factors share a homologous DNA binding domain presumably resulting from a common ancestry. In contrast, the C-terminal transcription modulation domains of both SMAD and NFI/CTF families do not show any sequence similarity. Based on the structural relationship of their DNA binding domains, we propose that the SMAD and NFI/CTF transcription factors belong to new superfamily of genes.

Amino Acid Sequence↗

PubMed1998

TOPAL: recombination detection in DNA and protein sequences.

UNLABELLED: TOPAL scans a multiple sequence alignment for evidence of recombinant sequences, prior to phylogenetic analysis. AVAILABILITY: The TOPAL package may be accessed at http://www.bioss.sari.ac.uk/grainne, and by anonymous ftp at ftp.bioss. sari.ac.uk in the directory pub/phylogeny/topal. CONTACT: grainne@bioss.sari.ac.uk

Computational Biology↗

PubMed1996

Database on the structure of large ribosomal subunit RNA.

Our database on large ribosomal subunit RNA contained 334 sequences in July, 1995. All sequences in the database are aligned, taking into account secondary structure. The aligned sequences are provided, together with incorporated secondary structure information, in several computer-readable formats. These data can easily be obtained through the World Wide Web. The files in the database are also available via anonymous ftp.

Animals↗

PubMed2002

DNA-binding activities of the HilC and HilD virulence regulatory proteins of Salmonella enterica serovar Typhimurium.

The HilC and HilD proteins of Salmonella enterica serovar Typhimurium are members of the AraC/XylS family of transcription regulators. They are encoded on Salmonella pathogenicity island 1 (SPI1) and control expression of the hilA gene, which encodes the major transcriptional activator for many genes encoded on SPI1 and elsewhere that contribute to invasion of host cells. Gel electrophoretic shift and DNase footprinting assays revealed that purified HilC and HilD proteins can bind to multiple regions in the hilA and hilC promoters and to a single region in the hilD promoter. Although both HilC and -D proteins can bind to the same DNA regions, they showed different dependencies on the sequence and lengths of their DNA targets. To identify the binding-sequence specificity of HilC and HilD, a series of single base substitutions changing each position in a DNA fragment corresponding to positions -92 to -52 of the hilC promoter was tested for binding to HilC and HilD in a gel shift DNA-binding assay. This mutational analysis in combination with sequence alignments allowed deduction of consensus sequences for binding of both proteins. The consensus sequences overlap but differ so that HilC can bind to both types of sites but HilD only to one. The hilA and hilC promoters contain multiple binding sites of each type, whereas the hilD promoter contains a site that binds HilC but not HilD without additional binding elements. The HilC and HilD proteins had no major effect on transcription from the hilA or hilD promoters using purified proteins in vitro but changed the choice of promoter at hilC. These results are consistent with a model derived from analysis of lacZ fusions stating that HilC and HilD enhance hilA expression by counteracting a repressing activity.

Bacterial Proteins↗

PubMed2000

Database analysis and gene discovery in pharmacogenetics.

The global genome research effort has resulted in the creation of extensive DNA and protein sequence databases that are a valuable resource for the identification of new genes and polymorphic variants of enzymes of pharmacogenetic interest. Previously undescribed members of gene families with novel functions and substrate specificities can be identified by database searching and sequence alignment strategies. Since the expressed sequence tag (EST) database contains sequences from many individuals, it can be searched for evidence of polymorphisms that can significantly influence enzyme function. The different approaches to these forms of analysis are reviewed and illustrated with examples from the glutathione transferase gene family.

Animals↗

PubMed1994

Exchangeable apolipoproteins of insects share a common structural motif.

Elucidation of the secondary structure of the exchangeable apolipoproteins has been hindered by the difficulty in producing crystals suitable for X-ray spectrographic analyses. Consequently, in order to analyze potential structure-function relationships in the family of insect exchangeable apolipoproteins, apolipophorins-III (apoLps-III), two apoLps-III cDNA clones, one from the palo verde beetle (Derobrachus geminatus) and one from the house cricket (Acheta domesticus), have been isolated and sequenced. Multiple sequence alignments of the deduced protein sequences with two previously reported apolipophorins-III from Manduca sexta and Locusta migratoria reveal low sequence identity, suggesting that these proteins are very old and are highly divergent. Computer-assisted predictions of protein structure and subsequent analyses, using the known secondary structure of Locusta migratoria apolipophorin-III as a control, indicate that these insect proteins are composed of five amphipathic helices with characteristics similar to those of the helical domains of the mammalian exchangeable apolipoproteins. Thus, although insect and vertebrate exchangeable apolipoproteins share a common function in assisting lipid transport, precise amino acid identity is less important than the common structural feature of multiple amphipathic helices. Moreover, because these proteins occur widely among insect species, even in those where flight is limited or absent, we hypothesize that apolipophorin-III has a more generalized function in lipid metabolism than had been previously proposed.

Amino Acid Sequence↗

PubMed1994

Isoprenyl diphosphate synthases: protein sequence comparisons, a phylogenetic tree, and predictions of secondary structure.

Isoprenyl diphosphate synthases are ubiquitous enzymes that catalyze the basic chain-elongation reaction in the isoprene biosynthetic pathway. Pairwise sequence comparisons were made for 6 farnesyl diphosphate synthases, 6 geranylgeranyl diphosphate synthases, and a hexaprenyl diphosphate synthase. Five regions with highly conserved residues, two of which contain aspartate-rich DDXX(XX)D motifs found in many prenyltransferases, were identified. A consensus secondary structure for the group, consisting mostly of alpha-helices, was predicted for the multiply aligned sequences from amino acid compositions, computer assignments of local structure, and hydropathy indices. Progressive sequence alignments suggest that the 13 isoprenyl diphosphate synthases evolved from a common ancestor into 3 distinct clusters. The most distant separation is between yeast hexaprenyl diphosphate synthetase and the other enzymes. Except for the chromoplastic geranylgeranyl diphosphate synthase from Capsicum annuum, the remaining farnesyl and geranylgeranyl diphosphate synthases segregate into prokaryotic/archaebacterial and eukaryotic families.

Alkyl and Aryl Transferases↗

PubMed2002

Estimating amino acid substitution models: a comparison of Dayhoff's estimator, the resolvent approach and a maximum likelihood method.

Evolution of proteins is generally modeled as a Markov process acting on each site of the sequence. Replacement frequencies need to be estimated based on sequence alignments. Here we compare three approaches: First, the original method by Dayhoff, Schwartz, and Orcutt (1978) Atlas Protein Seq. Struc. 5:345-352, secondly, the resolvent method (RV) by Müller and Vingron (2000) J. Comput. Biol. 7(6):761-776, and finally a maximum likelihood approach (ML) developed in this paper. We evaluate the methods using a highly divergent and inhomogeneous set of sequence alignments as an input to the estimation procedure. ML is the method of choice for small sets of input data. Although the RV method is computationally much less demanding it performs only slightly worse than ML. Therefore, it is perfectly appropriate for large-scale applications.

Algorithms↗