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PubMed2006

How strongly do sequence conservation patterns and empirical scales correlate with exposure patterns of transmembrane helices of membrane proteins?

Given the difficulty in determining high-resolution structures of helical membrane proteins, sequence-based prediction methods can be useful in elucidating diverse physiological processes mediated by this important class of proteins. Predicting the angular orientations of transmembrane (TM) helices about the helix axes, based on the helix parameters from electron microscopy data, is a classical problem in this regard. This problem has triggered the development of a number of different empirical scales. Recently, sequence conservation patterns were also made use of for improved predictions. Empirical scales and sequence conservation patterns (collectively termed as "prediction scales") have also found frequent applications in other research areas of membrane proteins: for example, in structure modeling and in prediction of buried TM helices. This trend is expected to grow in the near future unless there are revolutionary developments in the experimental characterization of membrane proteins. Thus, it is timely and imperative to carry out a comprehensive benchmark test over the prediction scales proposed so far to determine their pros and cons. In the current analysis, we use exposure patterns of TM helices as a golden standard, because if one develops a prediction scale that correlates perfectly with exposure patterns of TM helices, it will enable one to predict buried residues (or buried faces) of TM helices with an accuracy of 100%. Our analysis reveals several important points. (1) It demonstrates that sequence conservation patterns are much more strongly correlated with exposure patterns of TM helices than empirical scales. (2) Scales that were specifically parameterized using structure data (structure-based scales) display stronger correlation than hydrophobicity-based scales, as expected. (3) A nonnegligible difference is observed among the structure-based scales in their correlational property, suggesting that not every learning algorithm is equally effective. (4) A straightforward framework of optimally combining sequence conservation patterns and empirical scales is proposed, which reveals that improvements gained from combining the two sources of information are not dramatic in almost all cases. In turn, this calls for the development of fundamentally different scales that capture the essentials of membrane protein folding for substantial improvements.

Algorithms↗

PubMed2006

Large-scale cis-element detection by analysis of correlated expression and sequence conservation between Arabidopsis and Brassica oleracea.

The rapidly increasing amount of plant genomic sequences allows for the detection of cis-elements through comparative methods. In addition, large-scale gene expression data for Arabidopsis (Arabidopsis thaliana) have recently become available. Coexpression and evolutionarily conserved sequences are criteria widely used to identify shared cis-regulatory elements. In our study, we employ an integrated approach to combine two sources of information, coexpression and sequence conservation. Best-candidate orthologous promoter sequences were identified by a bidirectional best blast hit strategy in genome survey sequences from Brassica oleracea. The analysis of 779 microarrays from 81 different experiments provided detailed expression information for Arabidopsis genes coexpressed in multiple tissues and under various conditions and developmental stages. We discovered candidate transcription factor binding sites in 64% of the Arabidopsis genes analyzed. Among them, we detected experimentally verified binding sites and showed strong enrichment of shared cis-elements within functionally related genes. This study demonstrates the value of partially shotgun sequenced genomes and their combinatorial use with functional genomics data to address complex questions in comparative genomics.

Arabidopsis↗

PubMed1994

Study of the roles of proline 391 and a highly conserved sequence in the carboxyl-terminal region of members of the serpin family in the secretion of alpha 1-proteinase inhibitor.

Truncation of alpha 1-proteinase inhibitor prior to Pro391 prevents its secretion. This residue is the carboxyl terminus of a highly conserved sequence in serpins, suggesting that either Pro391 or the conserved sequence may serve as at least a part of a signal recognized by components of the secretory pathway. To evaluate these possibilities, we have determined the effects of replacement of Pro391 on the secretion of alpha 1-proteinase inhibitor and have examined the ability of the 9-residue conserved sequence to mediate secretion. We find that replacement of Pro391 with hydrophobic residues yields variants that are well secreted, but replacement with other classes of amino acids severely restricts secretion. These results show that while alpha 1-proteinase inhibitor is secreted most efficiently when proline occupies position 391, Pro391 is not an absolute requirement for its secretion. Our results show that the 9-amino acid conserved sequence found near the carboxyl termini of proteins of the serpin family is not sufficient to direct the secretion of alpha 1-proteinase inhibitor. We conclude that mutations affecting residue 391 and other positions in the conserved region lead to structural changes, possibly very minor, that influence the secretion of alpha 1-proteinase inhibitor.

Amino Acid Sequence↗

PubMed2003

Computational identification of protein coding potential of conserved sequence tags through cross-species evolutionary analysis.

The identification of conserved sequence tags (CSTs) through comparative genome analysis may reveal important regulatory elements involved in shaping the spatio-temporal expression of genetic information. It is well known that the most significant fraction of CSTs observed in human-mouse comparisons correspond to protein coding exons, due to their strong evolutionary constraints. As we still do not know the complete gene inventory of the human and mouse genomes it is of the utmost importance to establish if detected conserved sequences are genes or not. We propose here a simple algorithm that, based on the observation of the specific evolutionary dynamics of coding sequences, efficiently discriminates between coding and non-coding CSTs. The application of this method may help the validation of predicted genes, the prediction of alternative splicing patterns in known and unknown genes and the definition of a dictionary of non-coding regulatory elements.

Algorithms↗

PubMed1993

Direct selection of DNA sequences conserved between species.

An essential requirement in the analysis of genomes is the identification of functionally important sequence elements, which are often evolutionarily conserved. We describe here the development of a novel procedure for the selective isolation of conserved sequences which is based on hybridization of PCR-amplifiable DNA fragments from the whole genome of one species to biotinylated DNA from a genomic region of another species. The interspecies DNA hybrids are immobilized and the PCR-amplifiable DNA fragments are eluted, amplified and after further hybridization-amplification rounds cloned. This method was used for the generation of sublibraries of conserved sequences from mouse and pig DNA from regions corresponding to cosmids from the human Xq28 region. Mouse and pig homologs of sequences containing exons of known human genes, as well as exons from novel genes have been identified.

Animals↗

PubMed1997

Mammalian mitochondrial D-loop region structural analysis: identification of new conserved sequences and their functional and evolutionary implications.

This paper reports the first comprehensive analysis of Displacement loop (D-loop) region sequences from ten different mammalian orders. It represents a systematic evolutionary study at the molecular level on regulatory homologous regions in organisms belonging to a well defined class, mammalia, which radiated about 150 million years ago (Mya). We have aligned and analyzed 26 complete D-loop region sequences available in the literature and the fat dormouse sequence, recently determined in our laboratory. The novelty of our alignment consists of the extensive manual revision of the preliminary output obtained by computer program to optimize sequence similarity, particularly for the two peripheral domains displaying heterogeneity in length and the presence of repeated sequences. The multialignment is available at the WWW site: http://www.ba.cnr.it/dloop.html. Our comparative study has allowed us to identify new conserved sequence blocks present in all the species under consideration and events of insertion/deletion which have important implications in both functional and evolutionary aspects. In particular we have detected two blocks, about 60 bp long, extended termination associated sequences (ETAS1 and ETAS2) conserved in all the organisms considered. Evaluation against experimental work suggests a possible functional role of ETAS1 and ETAS2 in the regulation of replication and transcription and targeted experimental approaches. The analyses on conserved sequence blocks (CSBs) clearly indicate that CSB1 is the only very essential element, common to all mammalian mt genomes, while CSB2 and CSB3 could be involved in different though related functions, probably species specific, and thus more linked to nuclear mitochondrial coevolutionary processes. Our hypothesis on the different functional implications of the conserved elements, CSBs and TASs, reported so far as main regulatory signals, would explain the different conservation of these elements in evolution. Moreover the intra-order comparison of the D-loop regions highlights peculiar features useful to define the evolutionary dynamics of this region in closely related species.

Animals↗

PubMed1988

Identification of a nuclear factor that binds to a conserved sequence of the I-A beta gene.

Human and murine class II genes of the MHC show a striking homology 50 to 120 bp upstream of the transcription start site. This area is composed of two conserved sequences (a 13-mer and an 8-mer separated by 19 to 20 bp). Recently, these conserved sequences have been identified as cis-acting transcriptional regulatory elements. We have sought nuclear factors that bind specifically to an upstream fragment (-245 to +75 bp) of the murine I-A beta chain gene that contains the conserved sequences by application of a modified gel electrophoresis DNA binding assay. We report here the identification of a nuclear factor whose binding site overlaps the 8-mer conserved sequence. This factor is present in murine B and T lymphocytes, macrophages, mastocytes, fibroblasts, and human B lymphocytes and macrophages. The binding site was defined by using DNase I and dimethylsulfate protection assays. The putative binding sequence is closely related to the sequence, CCAAT, which is often found associated with the promoter of a gene and is recognized by the transcriptional factors CCAAT-binding transcription factor and nuclear factor I. Oligonucleotides that contain the binding site sequences for nuclear factor I and the alpha-globin CCAAT element, however, do not compete for binding of the nuclear factor to the sequence identified here, suggesting that, in spite of the similarity of the binding sequence, the nuclear factor identified in this report may be different. This nuclear protein may be one of the trans-acting factors that mediate transcription of class II genes.

Animals↗

PubMed1985

Studies on T. utilis tRNATyr variants with enzymatically altered D-loop sequences. I. Deletion of the conserved sequence Gm-G and its effects on aminoacylation and conformation.

Variants of T. utilis tRNATyr containing deletions or substitutions of nucleotides in the D-loop region have been prepared by several enzymatic reaction steps in vitro. Although these variants lack the "conserved" nucleotides Gm18-G19 in their D-loop, their tyrosine-accepting capacities are indistinguishable from that of the native tRNATyr. Thermal denaturation studies with tRNATyr variants lacking the Gm18-G19 sequence have revealed a biphasic nature of the melting profile, suggesting the loss of tertiary interactions between Gm18-G19 and somewhere in the molecule (probably in the T psi C-loop region). These results indicate that nucleotide sequences around Gm18-G19 (i.e. D16-D-Gm-G19 or Gm18-G-D-D21) themselves are not essential sites for the recognition of tRNATyr by T. utilis tyrosyl-tRNA synthetase and that tRNATyr variants with an apparently "relaxed" conformation still have full aminoacylation capacities at around 30 degrees C.

Acylation↗

PubMed2000

Transfer factors: identification of conserved sequences in transfer factor molecules.

BACKGROUND: Transfer factors are small proteins that "transfer" the ability to express cell-mediated immunity from immune donors to non-immune recipients. We developed a process for purifying specific transfer factors to apparent homogeneity. This allowed us to separate individual transfer factors from mixtures containing several transfer factors and to demonstrate the antigen-specificity of transfer factors. Transfer factors have been shown to be an effective means for correction of deficient cellular immunity in patients with opportunistic infections, such as candidiasis or recurrent Herpes simplex and to provide prophylactic immunity against varicella-zoster in patients with acute leukemia. MATERIALS AND METHODS: Transfer factors of bovine and murine origin were purified by affinity chromatography and high performance liquid chromatography. Cyanogen bromide digests were sequenced. The properties of an apparently conserved sequence on expression of delayed-type hypersensitivity by transfer factor recipients were assessed. RESULTS: A novel amino acid sequence, LLYAQDL/VEDN, was identified in each of seven transfer factor preparations. These peptides would not transfer expression of delayed-type hypersensitivity to recipients, which indicates that they are not sufficient for expression of the specificity or immunological properties of native transfer factors. However, administration of the peptides to recipients of native transfer factors blocked expression of delayed-type hypersensitivity by the recipients. The peptides were not immunosuppressive. CONCLUSIONS: These findings suggest that the peptides may represent the portion of transfer factors that binds to the "target cells" for transfer factors. Identification of these cells will be helpful in defining the mechanisms of action of transfer factors.

Amino Acid Sequence↗

PubMed1980

A study of the level of nucleotide sequence conservation between the RNAs of two types serotypes of foot-and-mouth disease virus.

The level of nucleotide sequence conservation between the RNAs of type A and type O foot-and-mouth disease virus (FMDV) has been compared by three methods. (I) RNA hybridization of fragments containing either the poly(C) tract at the 5' end of the RNA of the poly(A) tract at the 3' end of the RNA indicates that there is a similar level of sequence conservation (65% homology) across the genome. RNase T1 fingerprinting of these fragments did not show the presence of any long regions of completely conserved nucleotides apart from the poly(C) and the poly(A) tracts. (2) RNase T1 fingerprints of the RNA on the 5' side of the the poly(C) tract (the S fragment) show that there is more conservation in this region of the RNA than indicated by the hybridization results. (3) Direct nucleotide sequencing of the poly(C) tract and of the 54 nucleotides at the 5' end of the two genomes shows that there is considerable sequence conservation at the extreme 5' end of the RNA.

Aphthovirus↗

PubMed2003

New types of conserved sequence domains in DNA-binding regions of homing endonucleases.

We have identified four new types of short conserved sequence domains in homing endonucleases and related proteins. These domains are modular, appearing in various combinations. One domain includes a motif known by structure as a novel sequence-specific DNA-binding helix. Sequence similarity shows two other domains to be new types of helix-turn-helix DNA-binding domains. We term the new domains nuclease-associated modular DNA-binding domains (NUMODs).

Amino Acid Sequence↗

PubMed1996

Chromosomal integration dependent induction of junB by growth factors requires multiple flanking evolutionarily conserved sequences.

The junB locus contains nine flanking evolutionarily conserved sequences (FECS) that share 72% to 91% sequence identity between human and mouse. These FECS encompass the same regions of flanking DNA necessary for maximal mitogenic induction of junB. Most of the cis elements reported to date that affect junB regulation also reside within FECS. These observations suggest that the persistence of FECS through evolution reflects a necessary role in junB transcriptional regulation. In this report, we identify specific regulatory cis elements within junB FECS II and III and provide a quantitative analysis of the contribution made by these sequences to junB induction. These cis elements include a Serum Response Element (SRE), two Ets sites previously unrecognized as contributing to junB expression, and two novel Ets-linked motifs (ELMs). In general, mutating any single element significantly impairs junB induction. Moreover, the same mutations alter the structure of junB 5' flanking DNA within chromatin. Collectively, these results suggest that multiple proteins bound within FECS confederate to form a functional promoter complex, the activity of which is dependent upon a specific chromatin architecture.

Animals↗

PubMed2004

Sequential multiple functions of the conserved sequence in sequence-specific termination by T7 RNA polymerase.

Escherichia coli rrnB terminator t1 contains an RNA hairpin-dependent (class I) and a sequence-specific (class II) termination signal. The latter consists of an 8-bp conserved sequence (CS), TATCTGTT, immediately followed by an 8-bp T rich sequence. In this study, elongation complexes of T7 RNA polymerase at various positions of the class II signal and several mutant signals were obtained by stepwise walking on immobilized DNA templates free of the class I signal. Multiple CS-associated conformational changes were observed, starting at the beginning of the signal and occurring sequentially. When the complexes reach the first base pair of the CS-DNA duplex, which is downstream of the RNA-DNA heteroduplex, their stability, as measured by time-course retention of radiolabeled transcripts, markedly decreases. Further elongation leads to an abrupt change in polymerase-RNA interaction. Cross-linking of the polymerase to a 4-thio-UMP incorporated into RNA 8 nucleotides upstream of the 3' end and just upstream of the heteroduplex is initially strong but diminishes when the polymerase reaches the fourth base pair of the CS. After a further 7-nt elongation, the exposed single-stranded region of nontemplate strand is contracted; RNA in the upstream half of the heteroduplex becomes dissociated, and the CS-DNA duplex is reformed. During the next 5-nt elongation before termination, the CS duplex is prevented from translocation, and the contracted transcription bubble expands only downstream. These findings suggest that the CS duplex plays essential roles by successively binding to polymerase both downstream and upstream of the heteroduplex.

Base Sequence↗

PubMed2002

Sequence conservation in Ig-like domains: the role of highly conserved proline residues in the fibronectin type III superfamily.

The role of conserved proline residues in fibronectin type III (fnIII) domains is investigated. Surprisingly, none of the standard set of explanations for residue conservation applies. The proline residues are not apparently conserved for function, or stability, or to nucleate folding, or to promote stabilising interactions across domain boundaries. However, when the most highly conserved proline residues are mutated to alanine there is an increase in the rate of aggregation of a fnIII double-module construct. The results suggest that proline residues may be conserved at domain-domain boundaries in fnIII domains to prevent aggregation in multi-modular proteins.

Amino Acid Motifs↗

PubMed2000

Nephrocystin: gene expression and sequence conservation between human, mouse, and Caenorhabditis elegans.

Juvenile nephronophthisis, an autosomal recessive cystic kidney disease, is the primary genetic cause for chronic renal failure in children. The gene (NPHP1) for nephronophthisis type 1 has recently been identified. Its gene product, nephrocystin, is a novel protein of unknown function, which contains a src-homology 3 domain. To study tissue expression and analyze amino acid sequence conservation of nephrocystin, the full-length murine Nphp1 cDNA sequence was obtained and Northern and in situ hybridization analyses were performed for extensive expression studies. The results demonstrate widespread but relatively weak NPHP1 expression in the human adult. In the adult mouse there is strong expression in testis. This expression occurs specifically in cell stages of the first meiotic division and thereafter. In situ hybridization to whole mouse embryos demonstrated widespread and uniform expression at all developmental stages. Amino acid sequence conservation studies in human, mouse, and Caenorhabditis elegans show that in nephrocystin the src-homology 3 domain is embedded in a novel context of other putative domains of protein-protein interaction, such as coiled-coil and E-rich domains. It is concluded that for multiple putative protein-protein interaction domains of nephrocystin, sequence conservation dates back at least to Caenorhabditis elegans. The previously described discrepancy between widespread tissue expression and the restriction of symptoms to the kidney has now been confirmed by an in-depth expression study.

Adaptor Proteins, Signal Transducing↗

PubMed2025

FUSE-PhyloTree: linking functions and sequence conservation modules of a protein family through phylogenomic analysis.

SUMMARY: FUSE-PhyloTree is a phylogenomic analysis software for identifying local sequence conservation associated with the different functions of a multi-functional (e.g. paralogous or multi-domain) protein family. FUSE-PhyloTree introduces an original approach that combines advanced sequence analysis with phylogenetic methods. First, local sequence conservation modules within the family are identified using partial local multiple sequence alignment. Next, the evolution of the detected modules and known protein functions is inferred within the family's phylogenetic tree using three-level phylogenetic reconciliation and ancestral state reconstruction. As a result, FUSE-PhyloTree provides a gene tree annotated with both predicted sequence modules and ancestral gene functions, enabling the association of functions with specific sequence regions based on their co-emergence. AVAILABILITY AND IMPLEMENTATION: FUSE-PhyloTree is provided as Docker and Singularity images including all the required software tools. Images, source code, test data, and documentation are available at https://github.com/OcMalde/fuse-phylotree and https://zenodo.org/records/15855068.

Phylogeny↗

PubMed2000

Sequence conservation in kringle IV-type 2 repeats of the LPA gene.

We have studied the homology of repeating kringle IV-type 2 (K IV-type 2) elements of the LPA gene. Two K IV-type 2 genomic polymerase chain reaction (PCR) fragment libraries were constructed, one from an individual with high and one from an individual with low Lp(a) lipoprotein level. Only minor K IV-type 2 repeat length heterogeneity was observed. Sequence analysis data from the cloned K IV-type 2 repeats revealed a high degree of LPA sequence conservation in exons as well as in introns both within and between the two libraries. This sequence conservation of the IV-type 2 kringles is in agreement with our previously reported results of simultaneous 'batch' DNA sequence analyses of all the K IV-type 2 repeats from single individuals. Sequence data from the clones, combined with genomic DNA sequencing, revealed that the K IV-type 2 reading frame of exons 1 and 2 are extended into the conserved flanking introns by 519 base pairs (bp) and 312 bp, respectively. The theoretical coding capacity of the exon 1 extended open reading frame (ORF I) is three times larger (173 amino acids, aa) than the translated exon 1, and that of the extended open reading frame of exon 2 (ORF II) is about twice (104 aa) the length of exon 2. A central portion of the intron separating exons 1 and 2 also exhibited a high degree of sequence conservation, with the exception of a polymorphic CA repeat. Within the 61 K IV repeat clones analysed, 19 different CA repeat patterns with 12-18 CA dinucleotide repeats were observed. A comparison between the 37 clones from the individual with high Lp(a) lipoprotein level and the 24 clones from the individual with low Lp(a) lipoprotein level, revealed that seven of the CA repeat variants were present in both clone libraries. The observed high level of sequence conservation in K IV-type 2 exons and introns matches relevant areas of the plasminogen gene, and our findings fit with recent K IV-type 2 duplications and evolutionary selection pressure theories, although gene conversion events could also explain the findings. DNA sequences within K IV-type 2 appeared to have no influence on Lp(a) lipoprotein level.

Adolescent↗

PubMed1989

Specific discontinuities in Leishmania tarentolae minicircles map within universally conserved sequence blocks.

Specific discontinuities remaining in the daughter strands of newly synthesized minicircles from Crithidia fasciculata and Trypanosoma equiperdum have been shown to lie within conserved sequence blocks (CSBs) present in minicircles from all species of trypanosomes. The presence of ribonucleotides at the 5' ends of the L-strand in both cases suggests that the conserved sequences may constitute a replication origin. However, specific discontinuities have only been mapped in organisms having unusually homogeneous populations of minicircles. The specific nicks in minicircles from the heterogeneous population present in Leishmania tarentolae have now been mapped to predicted sites within the CSBs. These results are consistent with a universal mechanism of minicircle replication dictated by a conserve sequence motif present both in minicircles having a high degree of sequence heterogeneity as well as in relatively homogeneous populations.

Animals↗