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PubMed1999

Protein consensus sequence motifs.

The large number of protein consensus sequences that may be recognized without computer analysis are reviewed. These include the extensive range of known phosphorylation site motifs for protein kinases; metal binding sites for calcium, zinc, copper, and iron; enzyme active site motifs; nucleotide binding and covalent attachment sites for prosthetic groups, carbohydrate, and lipids. Of particular notes is the increasing realization of the importance for cellular regulation of protein-protein interaction motifs and sequences that target proteins to particular subcellular locations. This article includes an introduction to accessing the many suites of programs for analysis of protein structure, signatures of protein families, and consensus sequences that may be carried out on the internet.

Amino Acid Motifs↗
PubMed2006

Genome-wide mapping of ORC and Mcm2p binding sites on tiling arrays and identification of essential ARS consensus sequences in S. cerevisiae.

BACKGROUND: Eukaryotic replication origins exhibit different initiation efficiencies and activation times within S-phase. Although local chromatin structure and function influences origin activity, the exact mechanisms remain poorly understood. A key to understanding the exact features of chromatin that impinge on replication origin function is to define the precise locations of the DNA sequences that control origin function. In S. cerevisiae, Autonomously Replicating Sequences (ARSs) contain a consensus sequence (ACS) that binds the Origin Recognition Complex (ORC) and is essential for origin function. However, an ACS is not sufficient for origin function and the majority of ACS matches do not function as ORC binding sites, complicating the specific identification of these sites. RESULTS: To identify essential origin sequences genome-wide, we utilized a tiled oligonucleotide array (NimbleGen) to map the ORC and Mcm2p binding sites at high resolution. These binding sites define a set of potential Autonomously Replicating Sequences (ARSs), which we term nimARSs. The nimARS set comprises 529 ORC and/or Mcm2p binding sites, which includes 95% of known ARSs, and experimental verification demonstrates that 94% are functional. The resolution of the analysis facilitated identification of potential ACSs (nimACSs) within 370 nimARSs. Cross-validation shows that the nimACS predictions include 58% of known ACSs, and experimental verification indicates that 82% are essential for ARS activity. CONCLUSION: These findings provide the most comprehensive, accurate, and detailed mapping of ORC binding sites to date, adding to the emerging picture of the chromatin organization of the budding yeast genome.

Algorithms↗
PubMed1987

Comparison of the consensus sequence flanking translational start sites in Drosophila and vertebrates.

The previously presented consensus sequence for eukaryotic translation initiation sites by Kozak was derived substantially from vertebrate mRNA sequences. Drosophila nuclear genes exhibit a significantly different translation start consensus sequence. These differences probably do not represent mechanistic differences in translation initiation inasmuch as both taxa exhibit identical preferences and restrictions at the crucial -3 position. Using more conservative criteria for the assignment of consensus the following consensus sequences were derived: vertebrate--CANCAUG and Drosophila--CAAAACAUG.

Animals↗
PubMed1994

Identification of -R-X-(X)-S/T-X3-S/T- as consensus sequence motif for autophosphorylation-dependent protein kinase.

To identify consensus sequence motif for a new family of protein kinase termed autophosphorylation-dependent protein serine/threonine kinase (auto-kinase), we have tested several synthetic peptides. The well established protein serine/threonine kinases such as cAMP-dependent protein kinase, Ca2+/calmodulin-dependent protein kinase (CaM-kinase), and protein kinase C were found to be inactive toward phosphorylation of syntide-3 (RPRPASVPPSPSLSRHA), which turned out to be an excellent substrate only for auto-kinase, indicating that syntide-3 is a specific substrate for auto-kinase. Modification of syntide-3 to become RPRPASVPPS/T did not affect the activity of auto-kinase. By contrast, autokinase became rather or almost inactive when the peptide was modified to become RPRPASVPPA/G/F/K/R/D/E/Y, indicating that amino acid number 10 in syntide-3 is crucial to the sequence motif recognized by auto-kinase. Phosphorylation of myelin basic protein (MBP) by autokinase revealed that auto-kinase predominantly phosphorylates MBP on one particular site with RT-T(p)HYGS as the phosphorylation site sequence, which could not be phosphorylated by any other reported MBP kinases including cAMP-dependent protein kinase, CaM-kinase, protein kinase C, mitogen-activated protein kinase, and kinase FA/GSK-3. Taken together, the results provide initial evidence that -Arg-X-(X)-Ser/Thr-X3-Ser/Thr- may represent a unique consensus sequence motif specifically recognized by autophosphorylation-dependent protein kinase, a new family of multi-substrate/multifunctional protein serine/threonine kinase.

Amino Acid Sequence↗
PubMed1996

Generality of a functional initiator consensus sequence.

Transcriptional initiator (Inr) elements, like TATA boxes, are found in the core promoters of many eukaryotic protein-coding genes. To facilitate the dissection of transcription initiation mechanisms, and to identify Inr elements within known and newly-discovered genes, the precise DNA sequence requirements for Inr activity must be defined. Previously, we reported a preliminary Inr consensus sequence based on an extensive mutant analysis carried out in HeLa cell extracts. This analysis was limited, however, because it was performed only with an in vitro transcription assay and with the mutants in only one promoter context. In this study, we have assessed the general validity of the functional Inr consensus sequence by analyzing a selected set of mutants in additional promoter contexts and with both in vivo and in vitro assays. In addition, we analyzed the evolutionary conservation of the Inr consensus sequence by determining the sequence requirements for Inr function in Drosophila embryo extracts. The results demonstrate the generality and strict conservation among vertebrates and invertebrates of the Inr consensus sequence, Py Py A+1 N T/A Py Py.

Animals↗
PubMed2005

A linear programming approach for identifying a consensus sequence on DNA sequences.

MOTIVATION: Maximum-likelihood methods for solving the consensus sequence identification (CSI) problem on DNA sequences may only find a local optimum rather than the global optimum. Additionally, such methods do not allow logical constraints to be imposed on their models. This study develops a linear programming technique to solve CSI problems by finding an optimum consensus sequence. This method is computationally more efficient and is guaranteed to reach the global optimum. The developed method can also be extended to treat more complicated CSI problems with ambiguous conserved patterns. RESULTS: A CSI problem is first formulated as a non-linear mixed 0-1 optimization program, which is then converted into a linear mixed 0-1 program. The proposed method provides the following advantages over maximum-likelihood methods: (1) It is guaranteed to find the global optimum. (2) It can embed various logical constraints into the corresponding model. (3) It is applicable to problems with many long sequences. (4) It can find the second and the third best solutions. An extension of the proposed linear mixed 0-1 program is also designed to solve CSI problems with an unknown spacer length between conserved regions. Two examples of searching for CRP-binding sites and for FNR-binding sites in the Escherichia coli genome are used to illustrate and test the proposed method. AVAILABILITY: A software package, Global Site Seer for the Microsoft Windows operating system is available by http://www.iim.nctu.edu.tw/~cjfu/gss.htm

Algorithms↗
PubMed1994

The carboxyl domain of zinc fingers of the Evi-1 myeloid transforming gene binds a consensus sequence of GAAGATGAG.

Inappropriate expression of the Evi-1 zinc finger gene is associated with myeloid leukemia and myelodysplastic syndromes in mice and humans and has been hypothesized to contribute to pathology by blocking myeloid differentiation. Evi-1 contains two domains of zinc fingers, an amino-terminal domain of seven fingers and a carboxyl domain of three fingers. The first domain binds a consensus sequence of GA(C/T)AAGATAAGATAA in binding and amplication reactions or GATA repeat containing regions of genomic DNA. The experiments described here, establish a consensus sequence for the carboxyl domain of zinc fingers consisting of GAAGATGAG. Unlike the first domain, the consensus sequence established for the carboxyl domain is identical to that which would be predicted by the current rules relating to C2H2 zinc fingers and DNA recognition. Substitution of sequences in finger 8 with those in finger 9, demonstrate that the individual fingers bind the predicted region of the consensus sequence. In an attempt to engineer binding of constructs containing the carboxyl domain, a variety of mutations were made in the middle finger that would be predicted to change the consensus sequence in specific ways. Remarkably, most of the mutations were deleterious and destroyed specific DNA binding. Although Evi-1 contains potential transcriptional activation domains, it was not able to activate gene transcription from CAT constructs containing the consensus sequence.

Animals↗
PubMed1994

A murine coronavirus MHV-S isolate from persistently infected cells has a leader and two consensus sequences between the M and N genes.

A plaque-cloned mouse hepatitis virus mutant, MHV-S No. 8, was isolated from Ki-BALB cells persistently infected with MHV-S. The mRNAs 1 to 6 were larger in the mutant, whereas there was no difference between the two viruses in the size of the smallest mRNA, mRNA 7. Sequence analyses of the genomic RNA, mRNA 6, and mRNA 7 of the two viruses revealed that an additional 111 nt were inserted just upstream of the intergenic consensus sequence preceding the N gene in MHV-S No. 8. The inserted region consisted of two different parts; the 3'-most 30 nt corresponded to nucleotides 28 to 57 of the leader sequence and the 5'-most 81 nt corresponded to nucleotides 58 to 138 of mRNA 7. This structure of No. 8 was most likely generated by RNA-RNA recombination between genomic RNA and subgenomic RNA species. The nucleotide insertion in the intergenic sequence between genes M and N resulted in two consensus sequences separated by 111 nt. Primer extension analysis revealed that the amount of a slightly larger, subgenomic mRNA resulting from initiation of synthesis at the upstream consensus sequence was only 5% of the usual sized mRNA 7 initiated from the downstream consensus sequence.

Animals↗
PubMed2004

Alu's dimeric consensus sequence destabilizes its transcripts.

The effect that different regions of the Alu consensus sequence have upon the stability and accumulation of its RNA polymerase III (Pol III) directed transcripts was determined by transiently overexpressing Alu deletion and chimeric constructs in human 293 cells. Transcripts of the left Alu monomer are more stable than those of the full-length consensus sequence and any additional 3' sequence beyond the left monomer destabilizes the resulting transcript. Neither the middle A-rich region nor the 3' A-rich tail specifically affect the stability of Alu transcripts. However, the right monomer is inherently less stable than corresponding left monomer transcripts. Alu's dimeric structure and sequences peculiar to the right monomer each limit the stability and steady state accumulation of its transcripts. A host requirement to rapidly metabolize Alu RNA or restrict its abundance may have selected for these two features of the Alu consensus sequence.

Alu Elements↗
PubMed1983

Promoters regulated by the glnG (ntrC) and nifA gene products share a heptameric consensus sequence in the -15 region.

We have determined the nucleotide sequences of the Klebsiella pneumoniae nifL (regulation of N2 fixation genes) and the Escherichia coli glnA (glutamine synthetase) promoters. We compared these sequences with the published sequences of three other promoters that, like the nifL and glnA promoters, are activated by the general nitrogen regulators glnF (ntrA) and glnG (ntrC). The three promoters are the argTr (arginine transport) and dhuA (histidine transport) promoters of Salmonella typhimurium and the nifH (nitrogenase) promoter of Rhizobium meliloti. All five sequences (with at most one mismatch) contain the heptameric consensus sequence T-T-T-T-G-C-A. In the R. meliloti nifH and K. pneumoniae nifL promoters, in which the transcription initiation sites have been determined, the consensus sequence is situated in the -15 region. We recently reported that the K. pneumoniae nifA product, which activates nif genes, can substitute for the glnG (ntrC) product in activating promoters of several genes involved in nitrogen assimilation, including the nifL, the glnA, and the R. meliloti nifH promoters. It is likely that nifA also activates the S. typhimurium argTr and dhuA promoters. In contrast, the glnG product cannot substitute for the nifA product in the activation of the K. pneumoniae nifH (nitrogenase) promoter. Consistent with this latter observation, and supporting the conclusion that the T-T-T-T-G-C-A sequence is a regulatory site for glnG product activation, the K. pneumoniae nifH promoter (C-C-C-T-G-C-A) has only partial similarity with the T-T-T-T-G-C-A consensus sequence in the -15 region.

Amino Acid Sequence↗
PubMed1988

Defining the consensus sequences of E.coli promoter elements by random selection.

The consensus sequence of E.coli promoter elements was determined by the method of random selection. A large collection of hybrid molecules was produced in which random-sequence oligonucleotides were cloned in place of a wild-type promoter element, and functional -10 and -35 E.coli promoter elements were obtained by a genetic selection involving the expression of a structural gene. The DNA sequences and relative levels of function for -10 and -35 elements were determined. The consensus sequences determined by this approach are very similar to those determined by comparing DNA sequences of naturally occurring E.coli promoters. However, no strong correlation is observed between similarity to the consensus and relative level of function. The results are considered in terms of E.coli promoter function and of the general applicability of the random selection method.

Base Sequence↗
PubMed1997

Sp1- and octamer-consensus sequence binding proteins during lens fibre differentiation.

The pattern of factors binding to either the Sp1-consensus sequence or to the octamer sequence during in vitro rat lens fibre cell differentiation has been examined by electrophoretic mobility shift assays. With the Sp1-consensus sequence as probe, two major and four minor bands were seen. Three bands were present at all stages of differentiation, two are lost during terminal differentiation and one is present only in late differentiating cells. The octamer probe yielded three bands, which co-migrate with Oct2, Oct3 and Oct7. The exact identity of these factors has not been established. The Oct3-like band was detected only in epithelial cell extracts, the other two bands were also found in fibre cell extracts, whereby the intensity of the Oct2-like band decreased relative to that of the Oct7-like band during differentiation. In transfection studies, a rat gamma D-crystallin promoter in which the proximal activator has been replaced by a dimer of the Sp1-consensus sequence showed a gradual increase in activity with differentiation, in contrast, a similar construct with an octamer dimer was active only during late differentiation and mimicked the pattern of activation of the parental gamma D-crystallin promoter.

Animals↗
PubMed2001

Genetic interactions between the 5' and 3' splice site consensus sequences and U6 snRNA during the second catalytic step of pre-mRNA splicing.

The YAG/ consensus sequence at the 3' end of introns (the slash indicates the location of the 3' splice site) is essential for catalysis of the second step of pre-mRNA splicing. Little is known about the interactions formed by these three nucleotides in the spliceosome. Although previous observations have suggested that the G of the YAG/ interacts with the first nucleotide of the /GUA consensus sequence at the 5' end of the intron, additional interactions have not been identified. Here we report several striking genetic interactions between A+3 of the 5' /GUA with Y-3 of the 3' YAG/ and G50 of the highly conserved ACAGAG motif in U6 snRNA. Two mutations in U6 G50 of the ACAGAG can weakly suppress two mutations in A+3 of the 5' /GUA. This suppression is significantly enhanced upon the inclusion of a specific mutation Y-3 in the 3' YAG/. RNA analysis confirmed that the severe splicing defect observed in A+3 and Y-3 double mutants can be rescued to near wild-type levels by the mutations in U6 G50. The contributions of each mutation to the genetic interaction and the strong position specificity of suppression, combined with previous findings, support a model in which the 5' /GUA and the GAG of U6 function in binding the 3' YAG/ during the second catalytic step.

Base Sequence↗
PubMed1992

Mutagenic analysis of the coronavirus intergenic consensus sequence.

Previously, a system in which an intergenic region from mouse hepatitis virus (MHV) inserted into an MHV defective interfering (DI) RNA led to transcription of a subgenomic DI RNA in helper virus-infected cells was established. In the present study, a DI cDNA containing one UCUAAAC consensus sequence in the middle of the 0.3-kb-long intergenic region located between genes 6 and 7 was constructed. From this DI cDNA clone, 21 mutant DI RNAs were constructed so that each of the seven consensus sequence nucleotides was changed individually to the three alternative bases. These mutants were used to define how changes in the integrity of MHV transcription consensus sequence UCUAAAC affected mRNA transcription. Except for two mutants with the sequences UGUAAAC and UCGAAAC, all of the mutants supported efficient subgenomic DI RNA transcription. This indicated that MHV transcription regulation was sufficiently flexible to recognize altered consensus sequences. Next, these and other mutants were used to examine the leader-body fusion site on the subgenomic DI RNAs. Sequence analysis demonstrated that all subgenomic DI RNAs analyzed contained two pentanucleotide sequences; the first sequence seemed to be contributed by the leader, and the leader-body fusion most likely took place at either the first or the second nucleotide of the second sequence. This observation was not consistent with the proposed coronavirus transcription model (S. C. Baker and M. M. C. Lai, EMBO J. 9:4173-4179, 1990) which states that nucleotide mismatch can be corrected by RNA polymerase proofreading activity.

Base Sequence↗
PubMed1987

Detecting homology of distantly related proteins with consensus sequences.

A simple protocol is described that is suitable for the detection of distantly related members of a protein family. In this procedure, similarity to a consensus sequence is used to distinguish chance similarity from similarity due to common ancestry. The consensus sequence is constructed from the sequences of established members of a protein family and it incorporates features characteristic of the protein fold of this family: conserved residues, the pattern of variable and conserved segments, preferred location of gaps etc. The database is searched with the consensus sequence, using the unitary matrix or log odds matrix for scoring the alignments, with variable gap penalty. The advantage of the method is that it weights key residues, ignores sequence similarity in variable segments (thus partially eliminating "background noise" coming from chance similarity), distinguishes gaps disrupting conserved segments from those occurring in positions known to be tolerant of gap events. The utility of the method was demonstrated in the case of the protein family homologous with the internal repeats of complement B as well as the internal repeats identified in fibroblast proteoglycan PG40. The consensus sequence method succeeded in finding some new members of these protein families that could not be detected by earlier methods of sequence comparison.

Algorithms↗
PubMed1987

GTP-binding domain: three consensus sequence elements with distinct spacing.

A sequence comparison of nine functionally different GTP-binding protein families has yielded further information on the general characterization of the conservation and importance of amino acid sequences in the GTP-binding domain, including a consensus sequence composed of three consensus elements GXXXXGK, DXXG, and NKXD with consensus spacings of either 40-80 or approximately equal to 130-170 amino acid residues between the first and second elements and approximately 40-80 amino acid residues between the second and third sequence elements; the sequence NKXW in place of NKXD in the sequence element responsible for base specificity allows the use of ITP as well as GTP; dGTP can be used with essentially the same efficiency as GTP; signal transducing proteins and enzymes have been identified in the nine families; and family conservations allow the identification of the most probable consensus sequence element when more than one is present. Employing these features we have screened the protein sequence data base of the Protein Identification Resource and have identified only known GTP-binding proteins with the exception of protein 2C from foot-and-mouth disease virus as matching the consensus sequence. Based on this finding we predict that foot-and-mouth disease virus protein 2C binds GTP and, by analogy, that protein 2C from several related viruses (polio, rhino, encephalomyocarditis, and cowpea mosaic) will bind a nucleotide as part of its biologic activity.

Amino Acid Sequence↗
PubMed2001

Effect of intragenic rearrangement and changes in the 3' consensus sequence on NSP1 expression and rotavirus replication.

The nonpolyadenylated mRNAs of rotavirus are templates for the synthesis of protein and the segmented double-stranded RNA (dsRNA) genome. During serial passage of simian SA11 rotaviruses in cell culture, two variants emerged with gene 5 dsRNAs containing large (1.1 and 0.5 kb) sequence duplications within the open reading frame (ORF) for NSP1. Due to the sequence rearrangements, both variants encoded only C-truncated forms of NSP1. Comparison of these and other variants encoding defective NSP1 with their corresponding wild-type viruses indicated that the inability to encode authentic NSP1 results in a small-plaque phenotype. Thus, although nonessential, NSP1 probably plays an active role in rotavirus replication in cell culture. In determining the sequences of the gene 5 dsRNAs of the SA11 variants and wild-type viruses, it was unexpectedly found that their 3' termini ended with 5'-UGAACC-3' instead of the 3' consensus sequence 5'-UGACC-3', which is present on the mRNAs of nearly all other group A rotaviruses. Cell-free assays indicated that the A insertion into the 3' consensus sequence interfered with its ability to promote dsRNA synthesis and to function as a translation enhancer. The results provide evidence that the 3' consensus sequence of the gene 5 dsRNAs of SA11 rotaviruses has undergone a mutation causing it to operate suboptimally in RNA replication and in the expression of NSP1 during the virus life cycle. Indeed, just as rotavirus variants which encode defective NSP1 appear to have a selective advantage over those encoding wild-type NSP1 in cell culture, it may be that the atypical 3' end of SA11 gene 5 has been selected for because it promotes the expression of lower levels of NSP1 than the 3' consensus sequence.

Amino Acid Sequence↗
PubMed2004

A new definition for the consensus sequence of the peroxisome targeting signal type 2.

All organisms except the nematode Caenorhabditis elegans have been shown to possess an import system for peroxisomal proteins containing a peroxisome targeting signal type 2 (PTS2). The currently accepted consensus sequence for this amino-terminal nonapeptide is -(R/K)(L/V/I)X(5)(H/Q)(L/A)-. Some C.elegans proteins contain putative PTS2 motifs, including the ortholog (CeMeK) of human mevalonate kinase, an enzyme known to be targeted by PTS2 to mammalian peroxisomes. We cloned the gene for CeMeK (open reading frame Y42G9A.4) and examined the subcellular localization of CeMeK and of two other proteins with putative PTS2s at their amino termini encoded by the open reading frames D1053.2 and W10G11.11. All three proteins localized to the cytosol, confirming and extending the finding that C.elegans lacks PTS2-dependent peroxisomal protein import. The putative PTS2s of the proteins encoded by D1053.2 and W10G11.11 did not function in targeting to peroxisomes in yeast or mammalian cells, suggesting that the current PTS2 consensus sequence is too broad. Analysis of available experimental data on both functional and nonfunctional PTS2s led to two re-evaluated PTS2 consensus sequences: -R(L/V/I/Q)XX(L/V/I/H)(L/S/G/A)X(H/Q)(L/A)-, describes the most common variants of PTS2, while -(R/K)(L/V/I/Q)XX(L/V/I/H/Q)(L/S/G/A/K)X(H/Q)(L/A/F)-, describes essentially all variants of PTS2. These redefined PTS2 consensus sequences will facilitate the identification of proteins of unknown cellular localization as possible peroxisomal proteins.

Amino Acid Sequence↗