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PubMed1999

FORESST: fold recognition from secondary structure predictions of proteins.

MOTIVATION: A method for recognizing the three-dimensional fold from the protein amino acid sequence based on a combination of hidden Markov models (HMMs) and secondary structure prediction was recently developed for proteins in the Mainly-Alpha structural class. Here, this methodology is extended to Mainly-Beta and Alpha-Beta class proteins. Compared to other fold recognition methods based on HMMs, this approach is novel in that only secondary structure information is used. Each HMM is trained from known secondary structure sequences of proteins having a similar fold. Secondary structure prediction is performed for the amino acid sequence of a query protein. The predicted fold of a query protein is the fold described by the model fitting the predicted sequence the best. RESULTS: After model cross-validation, the success rate on 44 test proteins covering the three structural classes was found to be 59%. On seven fold predictions performed prior to the publication of experimental structure, the success rate was 71%. In conclusion, this approach manages to capture important information about the fold of a protein embedded in the length and arrangement of the predicted helices, strands and coils along the polypeptide chain. When a more extensive library of HMMs representing the universe of known structural families is available (work in progress), the program will allow rapid screening of genomic databases and sequence annotation when fold similarity is not detectable from the amino acid sequence. AVAILABILITY: FORESST web server at http://absalpha.dcrt.nih.gov:8008/ for the library of HMMs of structural families used in this paper. FORESST web server at http://www.tigr.org/ for a more extensive library of HMMs (work in progress). CONTACT: valedf@tigr.org; munson@helix.nih.gov; garnier@helix.nih.gov

Computer Simulation↗
PubMed1997

In vitro RNA binding of the hepatitis A virus proteinase 3C (HAV 3Cpro) to secondary structure elements within the 5' terminus of the HAV genome.

The secondary structure elements at the 5' nontranslated region (NTR) of the picornaviral RNAs can be divided functionally into two domains, one of which directs cap-independent translation, whereas the other is essential for viral RNA replication. For the latter, the formation of an RNA replication complex that involves particularly viral proteinase-containing polypeptides and cellular proteins has been shown (Andino R, Rieckhof GE, Achacoso PL, Baltimore D, 1993, EMBO J 12:3587-3598; Xiang W et al., 1995, RNA 1:892-904). To initiate studies on the formation of the hepatitis A virus (HAV) RNA replication complex, binding of the HAV proteinase 3Cpro and 3CD to secondary structure elements at the 5' and 3' NTR of the HAV RNA was investigated. Using mobility shift assay, UV crosslinking/ label transfer, and northwestern analysis, we show that both the HAV 3Cpro and the proteolytically inactive mutant bind to in vitro synthesized transcripts, suggesting that the RNA-binding site of the enzyme is separated spatially from its catalytic center. Weak interactions with HAV 3Cpro were found for individual secondary structure elements comprising less than 100 nt. RNA-binding specificity was unambiguous for transcripts comprising at least two stem-loops along with the polypyrimidine tract. Furthermore, competition experiments suggest that the 5' terminus of the HAV genome contains multiple binding sites for HAV 3Cpro. In contrast to poliovirus, binding capacity of HAV 3CD to RNA of the 5' NTR was not improved as compared to 3C. The data imply that, during the viral life cycle, HAV 3Cpro might serve replicative function(s) in addition to proteolysis of the viral polyprotein.

3C Viral Proteases↗
PubMed2005

Application of the local regression method interval partial least-squares to the elucidation of protein secondary structure.

The infrared amide bands are sensitive to the conformation of the polypeptide backbone of proteins. Since the backbone of proteins folds in complex spatial arrangements, the amide bands of these proteins result from the superimposition of vibration modes corresponding to the different types of structural motifs (alpha helices, beta sheets, etc.). Initially, band deconvolution techniques were applied to determine the secondary structure of proteins, i.e., the abundance of each structural motif in the polypeptide chain was directly related to the area of the suitable deconvolved vibration modes under the amide I band (1700-1600 cm(-1)). Recently, several multivariate regression methods have been used to predict the secondary structure of proteins as an alternative to the previous methods. They are based on establishing a relationship between a matrix of infrared protein spectra and another that includes their secondary structure, expressed as the fractions of the different structural motifs, determined from X-ray analysis. In this study, we investigated the use of the local regression method interval partial least-squares (iPLS) to seek improvements to the full-spectrum PLS and other regression methods. The local character of iPLS avoids the use of spectral regions that can introduce noise or that can be irrelevant for prediction and focuses on finding specific spectral ranges related to each secondary structure motif in all the proteins. This study has been applied to a representative protein data set with infrared spectra covering a large wavenumber range, including amides I-III bands (1700-1200 cm(-1)). iPLS has revealed new structural mode assignments related to less explored amide bands and has offered a satisfactory predictive ability using a small amount of selected specific spectral information.

Amides↗
PubMed2004

A distinct utility of the amide III infrared band for secondary structure estimation of aqueous protein solutions using partial least squares methods.

Fourier transform infrared spectroscopy is becoming an increasingly important method to study protein secondary structure. The amide I region of the protein infrared spectrum is the widely used region, whereas the amide III region has been comparatively neglected due to its low signal. Since there is no water interference in the amide III region and, more importantly, the different secondary structures of proteins have more resolved differences in their amide III spectra, it is quite promising to use the amide III region to determine protein secondary structure. In our current study, a partial least squares (PLS) method was used to predict protein secondary structures from the protein IR spectra. The IR spectra of aqueous solutions of 16 different proteins of known crystal structure have been recorded, and the amide I, the amide III, and the amide I combined with the amide III region of these proteins were used to set up the calibration set for the PLS algorithm. Our results correlate quite well with the data from X-ray studies, and the prediction from the amide III region is better than that from amide I or combined amide I and amide III regions.

Algorithms↗
PubMed2001

The requirement for eukaryotic initiation factor 4A (elF4A) in translation is in direct proportion to the degree of mRNA 5' secondary structure.

Eukaryotic initiation factor (elF) 4A functions as a subunit of the initiation factor complex elF4F, which mediates the binding of mRNA to the ribosome. elF4A possesses ATPase and RNA helicase activities and is the prototype for a large family of putative RNA helicases (the DEAD box family). It is thought that the function of elF4A during translation initiation is to unwind the mRNA secondary structure in the 5' UTR to facilitate ribosome binding. However, the evidence to support this hypothesis is rather indirect, and it was reported that elF4A is also required for the translation of mRNAs possessing minimal 5' UTR secondary structure. Were this hypothesis correct, the requirement for elF4A should correlate with the degree of mRNA secondary structure. To test this hypothesis, the effect of a dominant-negative mutant of mammalian elF4A on translation of mRNAs with various degrees of secondary structure was studied in vitro. Here, we show that mRNAs containing stable secondary structure in the 5' untranslated region are more susceptible to inhibition by the elF4A mutant. The mutant protein also strongly inhibits translation from several picornavirus internal ribosome entry sites (IRES), although to different extents. UV crosslinking of elF4F subunits and elF4B to the mRNA cap structure is dramatically reduced by the elF4A mutant and RNA secondary structure. Finally, the elF4A mutant forms a more stable complex with elF4G, as compared to the wild-type elF4A, thus explaining the mechanism by which substoichiometric amounts of mutant elF4A inhibit translation.

5' Untranslated Regions↗
PubMed1991

The secondary structure of protein G', a robust molecule.

The secondary structure of recombinant streptococcal Protein G' was predicted and compared with spectropolarimetric data. The predicted secondary structure consisted of 37 +/- 4% alpha-helix and 30 +/- 5% beta-sheet, whereas the values obtained from c.d. data were 29 +/- 2% alpha-helix and 41 +/- 3% beta-sheet. An alpha-helix-beta-sheet/turn-alpha-helix motif is conjectured to comprise the Fc-binding unit. The c.d. spectra in the near u.v. and far u.v. show that the Protein G' molecule is stable to heating at 100 degrees C and to extremes of pH (pH 1.5 to 11.0). The protein retained biological activity at these extremes. The molecule uncoils above pH 11.5 in a time-dependent fashion. Unfolding of the molecule in guanidinium chloride was monitored by c.d. and fluorescence emission; 3 M-guanidinium chloride was required to unfold the protein by 50%. The protein was completely unfolded in 5.5 M-guanidinium chloride and fully refolded with restoration of activity after removal of guanidinium chloride.

Amino Acid Sequence↗
PubMed1993

Thermal stability of protein secondary structure in Langmuir-Blodgett films.

The temperature dependence of the secondary structure of photosynthetic reaction centres from Rhodobacter sphaeroides in solution and in Langmuir-Blodgett film was studied by circular dichroism. It was shown that the secondary structure of the protein was not affected in Langmuir-Blodgett films by heating up to 200 degrees C, while in solution it was completely lost at 55 degrees C. Molecular order rather than decreased hydration degree was held responsible.

Circular Dichroism↗
PubMed2000

Evidence for partial secondary structure formation in the transition state for arc repressor refolding and dimerization.

Structure formation and dimerization are concerted processes in the refolding of Arc repressor. The integrity of secondary structure in the transition state of Arc refolding has been investigated here by determining the changes in equilibrium stability and refolding/unfolding kinetics for a set of Ala --> Gly mutations at residues that are solvent-exposed in the native Arc dimer. At some sites, reduced stability was caused primarily by faster unfolding, indicating that secondary structure at these positions is largely absent in the transition state. However, most of the Ala --> Gly substitutions in the alpha-helices of Arc and a triple mutant in the beta-sheet also resulted in decreased refolding rates, in some cases, accounting for the major fraction of thermodynamic destabilization. Overall, these results suggest that some regions of native secondary structure are present but incompletely formed in the transition state of Arc refolding and dimerization. Consolidation of this secondary structure, like close packing of the hydrophobic core, seems to occur later in the folding process. On average, Phi(F) values for the Ala --> Gly mutations were significantly larger than Phi(F) values previously determined for alanine-substitution mutants, suggesting that backbone interactions in the transition state may be stronger than side chain interactions. Mutations causing significant reductions in the Arc refolding rate were found to cluster in the central turn of alpha-helix A and in the first two turns of alpha-helix B. In the Arc dimer, these elements pack together in a compact structure, which might serve as nucleus for further folding.

Amino Acid Substitution↗
PubMed2003

On the algebraic representation of RNA secondary structures with G x U pairs.

Magarshak et al. represented an RNA molecule as a complex vector x and an RNA secondary structure gamma as a complex matrix Sgamma in such a way that the molecule represented by x was compatible with the secondary structure gamma if and only if Sgamma o x=x. They only considered Watson-Crick base pairs and their representation cannot be extended to allow for G x U pairs. In this paper we study a generalization of Magarshak's representation that allows for these pairs, and in particular we provide a family of algebraic structures where that generalization can be carried out. We also show that this representation can be used to compare secondary structures, through transfer matrices which transform the representation of one secondary structure into the representation of the other.

Base Pairing↗
PubMed1995

The secondary structure of the adenovirus-2 L4 polyadenylation domain: evidence for a hairpin structure exposing the AAUAAA signal in its loop.

The secondary structure of the adenovirus-2 L4 polyadenylation domain was established using enzymatic attacks and chemical modifications. This domain is characterized by the co-existence of several variants including stem-loop structures of low stability such that its secondary structure is clearly distinct from that of the upstream sequence which harbors large stable hairpin structures. The L4 polyadenylation site is located in a free single-stranded region and the AAUAAA signal is exposed in the 14 nucleotide loop of a hairpin structure with a six-base-pair stem. The 5' arm of this stem includes six nucleotides of a previously identified upstream efficiency element (USEa), whose deletion or substitution reduces cleavage-polyadenylation efficiency by 50%. Several evidences suggest that a signal hairpin structure may be important for polyadenylation. First, the AAUAAA signal is well exposed to enzymes and reagents in its two co-existing variants, suggesting that it is also accessible to cleavage-polyadenylation factors. Second, the disruption of the stem induces a 50% decrease of cleavage efficiency in vitro. Third, the reduction of the size of the loop to five nucleotides reduces cleavage efficiency by 90%. Fourth, polyadenylation domains of other origins can be folded into hairpin structures harboring the AAUAAA signal in their loop. We propose that one of the functions of an upstream efficiency element could be to participate in the presentation of the signal to trans-acting factors.

Adenovirus E3 Proteins↗
PubMed2006

Model for folding and aggregation in RNA secondary structures.

We study the statistical mechanics of RNA secondary structures designed to have an attraction between two different types of structures as a model system for heteropolymer aggregation. The competition between the branching entropy of the secondary structure and the energy gained by pairing drives the RNA to undergo a "temperature independent" second order phase transition from a molten to an aggregated phase. The aggregated phase thus obtained has a macroscopically large number of contacts between different RNAs. The partition function scaling exponent for this phase is theta approximately 1/2 and the crossover exponent of the phase transition is nu approximately 5/3. The relevance of these calculations to the aggregation of biological molecules is discussed.

Models, Chemical↗
PubMed1993

Peptides secondary structure prediction with neural networks: a criterion for building appropriate learning sets.

Artificial neural networks have been recently applied with success for protein secondary structure prediction. So far, one of the two main aspects on which neural net performance depends, the topology of the net, has been considered. The present work addresses the other main aspect, the building up of the learning set. We present a criterion to build up suitable learning sets based on the alpha-helix percentage. Starting from a set of several well known proteins, we formed 7 groups of proteins with similar helix percentages and we used them for the learning of the same neural net. We found that the best secondary structure prediction for each of the tested proteins (not belonging to the initial set) was the one obtained using the learning set whose helix percentage was closest to that of the tested protein. The accuracy of correct prediction of our method on three types of secondary structure (alpha-helix, beta-sheet and coil), has been compared with the accuracy of other secondary structure prediction methods.

Algorithms↗
PubMed1991

Fourier transform infrared spectroscopic study of Ca2+ and membrane-induced secondary structural changes in bovine prothrombin and prothrombin fragment 1.

Fourier transform infrared (FTIR) spectroscopy was used to monitor secondary structural changes associated with binding of bovine prothrombin and prothrombin fragment 1 to acidic lipid membranes. Prothrombin and prothrombin fragment 1 were examined under four different conditions: in the presence of (a) Na2EDTA, (b) 5 mM CaCl2, and in the presence of CaCl2 plus membranes containing 1-palmitoyl-2-oleoyl-3-sn-phosphatidylcholine (POPC) in combination with either (c) bovine brain phosphatidyl-serine (bovPS) or (d) 1,2-dioleoyl-phosphatidylglycerol (DOPG). The widely reported Ca(2+)-induced conformational change in bovine prothrombin fragment 1 was properly detected by our procedures, although Ca(2+)-induced changes in whole prothrombin spectra were too small to be reliably interpreted. Binding of prothrombin in the presence of Ca2+ to procoagulant POPC/bovPS small unilamellar vesicles produced an increase in ordered secondary structures (2% and 3% increases in alpha-helix and beta-sheet, respectively) and a decrease of random structure (5%) as revealed by spectral analysis on both the original and Fourier-self-deconvolved data and by difference spectroscopy with the undeconvolved spectra. Binding to POPC/DOPG membranes, which are less active as procoagulant membranes, produced no detectable changes in secondary structure. In addition, no change in prothrombin fragment 1 secondary structure was detectable upon binding to either POPC/bovPS or POPC/DOPG membranes. This indicates that a membrane-induced conformational change occurs in prothrombin in the nonmembrane-binding portion of the molecule, part of which is activated to form thrombin, rather than in the membrane-binding fragment 1 region. The possible significance of this conformational change is discussed in terms of differences between the procoagulant activities of different acidic lipid membranes.

Animals↗
PubMed2006

An analysis of intron positions in relation to nucleotides, amino acids, and protein secondary structure.

We present an analysis of intron positions in relation to nucleotides, amino acid residues, and protein secondary structure. Previous work has shown that intron sites in proteins are not randomly distributed with respect to secondary structures. Here we show that this preference can be almost totally explained by the nucleotide bias of splice site machinery, and may well not relate to protein stability or conformation at all. Each intron phase is preferentially associated with its own set of residues: phase 0 introns with lysine, glutamine, and glutamic acid before the intron, and valine after; phase 1 introns with glycine, alanine, valine, aspartic acid, and glutamic acid; and phase 2 introns with arginine, serine, lysine, and tryptophan. These preferences can be explained principally on the basis of nucleotide bias at intron locations, which is in accordance with previous literature. Although this work does not prove that introns are inserted into genomes at specific proto-splice sites, it shows that the nucleotide bias surrounding introns, however it originally occurred, explains the observed correlations between introns and protein secondary structure.

Amino Acids↗
PubMed1990

Saccharomyces cerevisiae U1 small nuclear RNA secondary structure contains both universal and yeast-specific domains.

The five small nuclear RNAs (snRNAs) involved in mammalian pre-mRNA splicing (U1, U2, U4, U5, and U6) are well conserved in length, sequence, and especially secondary structure. These five snRNAs from Saccharomyces cerevisiae show notable size and sequence differences from their metazoan counterparts. This is most striking for the large S. cerevisiae U1 and U2 snRNAs, for which no secondary structure models currently exist. Because of the importance of U1 snRNA in the early steps of "spliceosome" assembly, we wanted to compare the highly conserved secondary structure of metazoan U1 snRNA (approximately 165 nucleotides) with that of S. cerevisiae U1 snRNA (568 nucleotides). To this end, we have cloned and sequenced the U1 gene from two other yeast species possessing large U1 RNAs. Using computer-derived structure predictions, phylogenetic comparisons, and structure probing, we have arrived at a secondary structure model for S. cerevisiae U1 snRNA. The results show that most elements of higher eukaryotic U1 snRNA secondary structure are conserved in S. cerevisiae. The hundreds of "extra" nucleotides of yeast U1 RNA, also highly structured, suggest that large insertions and/or deletions have occurred during the evolution of the U1 gene.

Base Sequence↗
PubMed2005

Compilation of mRNA polyadenylation signals in Arabidopsis revealed a new signal element and potential secondary structures.

Using a novel program, SignalSleuth, and a database containing authenticated polyadenylation [poly(A)] sites, we analyzed the composition of mRNA poly(A) signals in Arabidopsis (Arabidopsis thaliana), and reevaluated previously described cis-elements within the 3'-untranslated (UTR) regions, including near upstream elements and far upstream elements. As predicted, there are absences of high-consensus signal patterns. The AAUAAA signal topped the near upstream elements patterns and was found within the predicted location to only approximately 10% of 3'-UTRs. More importantly, we identified a new set, named cleavage elements, of poly(A) signals flanking both sides of the cleavage site. These cis-elements were not previously revealed by conventional mutagenesis and are contemplated as a cluster of signals for cleavage site recognition. Moreover, a single-nucleotide profile scan on the 3'-UTR regions unveiled a distinct arrangement of alternate stretches of U and A nucleotides, which led to a prediction of the formation of secondary structures. Using an RNA secondary structure prediction program, mFold, we identified three main types of secondary structures on the sequences analyzed. Surprisingly, these observed secondary structures were all interrupted in previously constructed mutations in these regions. These results will enable us to revise the current model of plant poly(A) signals and to develop tools to predict 3'-ends for gene annotation.

3' Untranslated Regions↗
PubMed1999

Prediction of protein secondary structure content.

All existing algorithms for predicting the content of protein secondary structure elements have been based on the conventional amino-acid-composition, where no sequence coupling effects are taken into account. In this article, an algorithm was developed for predicting the content of protein secondary structure elements that was based on a new amino-acid-composition, in which the sequence coupling effects are explicitly included through a series of conditional probability elements. The prediction was examined by a self-consistency test and an independent dataset test. Both indicated a remarkable improvement obtained when using the current algorithm to predict the contents of alpha-helix, beta-sheet, beta-bridge, 3(10)-helix, pi-helix, H-bonded turn, bend and random coil. Examples of the improved accuracy by introducing the new amino-acid-composition, as well as its impact on the study of protein structural class and biologically function, are discussed.

Algorithms↗
PubMed1992

Predictions of the secondary structure and antigenicity of human and bovine tropoelastins.

Secondary structure and antigenicity predictive methods have been applied to the sequences of human and bovine tropoelastins in order to have some insight into the molecular structure of its insoluble counterpart, i.e., elastin. For both tropoelastins, all the predictions yielded 11 major regions, in which the pleated conformation was predominant, separated by 10 strong helical segments of various lengths located within alanyl rich regions of the chains. The overall conformations of human and bovine tropoelastins were estimated to contain 18 +/- 5% alpha-helices, 63 +/- 17% beta-sheets, 13 +/- 13% beta-turns and 6 +/- 6% random coil. For both tropoelastins, antigenicity predictions indicated the presence of seven synthetic decapeptides corresponding to continuous linear epitopes of the molecule. Some of the predicted epitopes are located in the same regions in both species while others are not. These predictions have allowed us to propose an alpha/beta conformation for tropoelastin. Therefore this extracellular matrix macromolecule might be more structured (10 helical segments for about 18% of the overall structure) than previously suggested.

Algorithms↗