Biomedical subjects
Publications and source records attributed to R B Russell.
Recent successes show that, in certain circumstances, protein secondary structures can be predicted with high accuracy. How far are we from being able to predict the complete structure of a protein from its sequence?
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The automatic identification of protein domains from coordinates is the first step in the classification of protein folds and hence is required for databases to guide structure prediction. Most algorithms encode a single concept based and sometimes do not yield assignments that are consistent with the generally accepted perception. Our development of an automatic approach to identify reliably domains from protein coordinates is described. The algorithm is benchmarked against a manual identification of the domains in 284 representative protein chains. The first step is the domain assignment by distance (DAD) algorithm that considers the density of inter-residue contacts represented in a contact matrix. The algorithm yields 85% agreement with the manual assignment. The paper then considers how the reliability of these assignments could be evaluated. Finally the use of structural comparisons using the STAMP algorithm to validate domain assignment is reported on a test case.
Side-chain to side-chain contacts, accessibility, secondary structure and RMS deviation were compared within 607 pairs of proteins having similar three-dimensional (3D) structures. Three types of protein 3D structural similarities were defined: type A having sequence and usually functional similarity; type B having functional, but no sequence similarity; and type C having only 3D structural similarity. Within proteins having little or no sequence similarity (types B and C), structural features frequently had a degree of conservation comparable to dissimilar 3D structures. Despite similar protein folds, as few as 30% of residues within similar protein 3D structures can form a common core. RMS deviations on core C alpha atoms can be as high as 3.2 A. Similar protein structures can have secondary structure identities as low as 41%, which is equivalent to that expected by chance. By defining three categories of amino acid accessibility (buried, half buried and exposed), some similar protein 3D structures have as few as 30% of positions in the same category, making them indistinguishable from pairs of dissimilar protein structures. Similar structures can also have as few as 12% of common side-chain to side-chain contacts, and virtually no similar energetically favourable side-chain to side-chain interactions. Complementary changes are defined as structurally equivalent pairs of interacting residues in two structures with energetically favourable but different side-chain interactions. For many proteins with similar three-dimensional structures, the proportion of complementary changes is near to that expected by chance, suggesting that many similar structures have fundamentally different stabilising interactions. All of the results suggest that proteins having similar 3D structures can have little in common apart from a scaffold of core secondary structures. This has profound implications for methods of protein fold detection, since many of the properties assumed to be conserved across similar protein 3D structures (e.g. accessibility, side-chain to side-chain contacts, etc.) are often unconserved within weakly similar (i.e. type B and C) protein 3D structures. Little difference was found between type B and C similarities suggesting that the structure of similar proteins can evolve beyond recognition even when function is conserved. Our findings suggest that it is more general features of protein structure, such as the requirements for burial of hydrophobic residues and exposure of polar residues, rather than specific residue-residue interactions that determine how well a particular sequence adopts a particular fold.(ABSTRACT TRUNCATED AT 400 WORDS)
The expected best residue-by-residue accuracies for secondary structure prediction from multiple protein sequence alignment have been determined by an analysis of known protein structural families. The results show substantial variation is possible among homologous protein structures, and that 100% agreement is unlikely between a consensus prediction and one member of a protein structural family. The study provides the range of agreement to be expected between a perfect secondary structure prediction from a multiple alignment and each protein within the alignment. The results of this study overcome the difficulties inherent in the use of residue-by-residue accuracy for assessing the quality of consensus secondary structure predictions. The accuracies of recent consensus predictions for the annexins, SH2 domains and SH3 domains fall within the expected range for a perfect prediction.
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Src homology 2 (SH2) regions are short (approximately 100 amino acids), non-catalytic domains conserved among a wide variety of proteins involved in cytoplasmic signaling induced by growth factors. It is thought that SH2 domains play an important role in the intracellular response to growth factor stimulation by binding to phosphotyrosine containing proteins. In this paper we apply the techniques of multiple sequence alignment, secondary structure prediction and conservation analysis to 67 SH2 domain amino acid sequences. This combined approach predicts seven core secondary structure regions with the pattern beta-alpha-beta-beta-beta-beta-alpha, identifies those residues most likely to be buried in the hydrophobic core of the native SH2 domain, and highlights patterns of conservation indicative of secondary structural elements. Residues likely to be involved in phosphotyrosine binding are shown and orientations of the predicted secondary structures suggested which could enable such residues to cooperate in phosphate binding. We propose a consensus pattern that encapsulates the principal conserved features of the SH2 domains. Comparison of the proposed SH2 domain of akt to this pattern shows only 12/40 matches, suggesting that this domain may not exhibit SH2-like properties.
An algorithm is presented for the accurate and rapid generation of multiple protein sequence alignments from tertiary structure comparisons. A preliminary multiple sequence alignment is performed using sequence information, which then determines an initial superposition of the structures. A structure comparison algorithm is applied to all pairs of proteins in the superimposed set and a similarity tree calculated. Multiple sequence alignments are then generated by following the tree from the branches to the root. At each branchpoint of the tree, a structure-based sequence alignment and coordinate transformations are output, with the multiple alignment of all structures output at the root. The algorithm encoded in STAMP (STructural Alignment of Multiple Proteins) is shown to give alignments in good agreement with published structural accounts within the dehydrogenase fold domains, globins, and serine proteinases. In order to reduce the need for visual verification, two similarity indices are introduced to determine the quality of each generated structural alignment. Sc quantifies the global structural similarity between pairs or groups of proteins, whereas Pij' provides a normalized measure of the confidence in the alignment of each residue. STAMP alignments have the quality of each alignment characterized by Sc and Pij' values and thus provide a reproducible resource for studies of residue conservation within structural motifs.
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This article describes investigations of several aspects of the molecular biology of the human renin gene and the three-dimensional structure of renin and its precursor, prorenin. Because of the importance of the RAS in hypertension, heart failure, renal failure, and possibly other disorders such as atherosclerosis, it is critical to understand the detailed control of this system. This control involves regulation at the transcriptional level, folding of prorenin, sorting of prorenin to a regulated pathway where it is proteolytically cleaved to renin and released in response to secretogogues, constitutive release of uncleaved prorenin, and nonproteolytic activation of prorenin. Currently there is great interest not only in the control of renin in the kidney, the sole source of circulating renin, but also at extrarenal sites where RAS activity may regulate cardiovascular functions. The renin gene was found to be expressed significantly in the renal juxtaglomerular cells and several other cell types. Most tissue culture cells did not express the gene; exceptions were cultured SK-LMS-1 cells and cAMP-stimulated human lung fibroblasts. Cultured human uterine-placental cells expressed the human renin gene at levels higher than in other cell types assessed. Renin mRNA had the same start site in the placental cells as the kidney and was regulated by calcium ionophores and cAMP. Thus, these cells provide primary nontransformed human cells to study the homologous human promoter. Transfected renin promoters showed cell type-specific expression and cAMP responsiveness in these cells in constructs containing as few as 102 bp of 5'-flanking DNA. DNA upstream from this appears to contain an inhibitory element(s) that may have some tissue specificity in its distribution. The cAMP response is not due to cAMP induction of a transcription factor that secondarily affects the renin promoter. A novel element may be involved, since the promoter does not contain a CRE element that mediates many cAMP responses, and the cells do not appear to respond to another known cAMP-responsive transcription factor, AP-2. Studies with transfected vectors expressing a mutant cAMP-responsive protein kinase A regulatory subunit suggest that cAMP is not responsible for basal renin promoter activity in the placental cells. By contrast, cAMP induces in essence gene activation in WI26VA4 transformed human lung fibroblasts in which renin mRNA levels increase by up to 150-fold in response to forskolin. Thus, cAMP may activate renin gene expression under certain circumstances and tissue-specific renin gene expression may be directed by more than one mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)
Injectable collagen is an extremely effective treatment for the correction of facial soft tissue deformities due to minor contour irregularities. A specially trained nurse can be an integral part of the collagen treatment program in a plastic surgery office. The nurse must be motivated to inject collagen, must have the support of the supervising plastic surgeon, and must have confidence in his or her ability to make appropriate aesthetic judgements.
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Thirteen new analogs of 2,4-diamino-5(p-chlorophenyl)-6-ethylpyrimidine (Daraprim, pyrimethamine) in which the alph position of the 6-ethyl substituent was modified were prepared. The respective oxygens analogs (ketals, ketone, alcohol), the dimethyl hydrazone, and the nitrone displayed activities in the range of 1/4 to 1/16 that of pyrimethamine toward Plasmodium berghei in mice. The therapeutic ratios of some of these compounds may be slightly better than that of pyrimethamine.
Three cases are described in each of which an HLA identical kidney transplant from a brother was rejected forcefully by the recipient and only one graft survived for more than a year. Rejection of this type is most unusual with well matched grafts and may have been triggered by a system of major antigens that are unassociated with those that are currently recognised.
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