RESUMEN
The prion protein displays a unique structural ambiguity in that it can adopt multiple stable conformations under physiological conditions. In our view, this puzzling feature resulted from a sudden environmental change in evolution when the prion, previously an integral membrane protein, got expelled into the extracellular space. Analysis of known vertebrate prions unveils a primordial transmembrane protein encrypted in their sequence, underlying this relocalization hypothesis. Apparently, the time elapsed since this event was insufficient to create a "minimally frustrated" sequence in the new milieu, probably due to the functional constraints set by the importance of the very flexibility that was created in the relocalization. This scenario may explain why, in a structural sense, the prion protein is still en route toward becoming a foldable globular protein.
Asunto(s)
Evolución Molecular , Priones/química , Priones/genética , Conformación ProteicaRESUMEN
A new, simple method for predicting transmembrane segments in integral membrane proteins has been developed. It is based on low-stringency dot-plots of the query sequence against a collection of non-homologous membrane proteins using a previously derived scoring matrix [Cserzö et al., 1994, J. Mol. Biol., 243, 388-396]. This so-called dense alignment surface (DAS) method is shown to perform on par with earlier methods that require extra information in the form of multiple sequence alignments or the distribution of positively charged residues outside the transmembrane segments, and thus improves prediction abilities when only single-sequence information is available or for classes of membrane proteins that do not follow the 'positive inside' rule.
Asunto(s)
Proteínas de la Membrana/análisis , Células Procariotas/química , Estructura Secundaria de Proteína , Alineación de Secuencia/métodos , Membrana Celular/química , Biología Computacional , Modelos Moleculares , Homología de Secuencia de AminoácidoRESUMEN
In this paper an algorithm which locates helical transmembrane segments is described. It is shown that given the location of transmembrane helices of a protein, corresponding helices in another membrane related protein can be pinpointed. The method seems to be extremely insensitive to sequence identity but highly sensitive to the property of a sequence to assume transmembrane helical structure. As an example, using the present method, a sequence alignment between bacteriorhodopsin and human rhodopsin is carried out and it provides a good starting point for homology modeling of this G-protein coupled receptor. It is difficult to obtain this particular alignment using the traditional methods because of poor sequence homology. There are indications that hint at the broader range of applicability of the presented method.
Asunto(s)
Algoritmos , Proteínas de la Membrana/química , Estructura Secundaria de Proteína , Alineación de Secuencia/métodos , Secuencia de Aminoácidos , Bacteriorodopsinas/química , Humanos , Datos de Secuencia Molecular , Proteínas del Complejo del Centro de Reacción Fotosintética/química , Rodopsina/químicaRESUMEN
The existence of an endogenous high affinity interleukin 1 receptor antagonist (IL-1ra) suggests that this molecule lacks some structural motif(s) which are present in the closely homologous agonist interleukin 1 beta (IL-1 beta) and which serve as the 'agonist switch' causing signal transduction by the agonist-receptor complex. The primary sequence alignment of IL-1 beta and IL-1ra sequences from different species reveals a six amino acid long motif that is quasi conserved among IL-1 beta sequences, but is missing from the IL-1ra sequences. The three-dimensional structure of human IL-1 beta was used as a template for building structural models of deletion mutants (delta SND 52-54 and delta EESNDK 50-55) using molecular graphics. These models indicated that the middle three residues SND 52-54 from the EESNDK 50-55 loop may be deleted without causing major changes in the tertiary structure of the mutant as compared to that of IL-1 beta. Residues SND 52-54 from the above loop were deleted. When compared with IL-1 beta the IL-1 beta-delta SND analog (delta SND 52-54) binds with the same affinity to type 2 IL-1 receptor but with a more than 10-fold lower affinity to type 1 IL-1 receptor. Despite of this small decrease in affinity at the type 1 receptor the delta SND 52-54 has a 1000-fold lower biological activity than IL-1 beta when tested in a thymocyte activating factor assay.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Interleucina-1/química , Interleucina-1/metabolismo , Receptores de Interleucina-1/metabolismo , Sialoglicoproteínas/química , Sialoglicoproteínas/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Unión Competitiva , Bovinos , Cartilla de ADN , Humanos , Proteína Antagonista del Receptor de Interleucina 1 , Ligandos , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis , Estructura Secundaria de Proteína , Conejos , Ratas , Receptores de Interleucina-1/antagonistas & inhibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Eliminación de Secuencia , Homología de Secuencia de Aminoácido , OvinosRESUMEN
SBASE 2.0 is the second release of SBASE, a collection of annotated protein domain sequences. SBASE entries represent various structural, functional, ligand-binding and topogenic segments of proteins [Pongor, S. et al. (1993) Prot. Eng., in press]. This release contains 34,518 entries provided with standardized names and it is cross-referenced to the major protein and nucleic acid databanks as well as to the PROSITE catalog of protein sequence patterns [Bairoch, A. (1992) Nucl. Acids Res., 20 suppl, 2013-2018]. SBASE can be used for establishing domain homologies using different database-search tools such as FASTA [Lipman and Pearson (1985) Science, 227, 1436-1441], FASTDB [Brutlag et al. (1990) Comp. Appl. Biosci., 6, 237-245] or BLAST3 [Altschul and Lipman (1990) Proc. Natl. Acad. Sci. USA, 87, 5509-5513] which is especially useful in the case of loosely defined domain types for which efficient consensus patterns can not be established. SBASE 2.0 and a set of search and retrieval tools are freely available on request to the authors or by anonymous 'ftp' file transfer from mean value of ftp.icgeb.trieste.it.
Asunto(s)
Bases de Datos Factuales , Conformación Proteica , Proteínas/química , Homología de Secuencia de Aminoácido , Secuencia de Aminoácidos , Animales , Humanos , Datos de Secuencia Molecular , Secuencias Repetitivas de Ácidos Nucleicos , Programas InformáticosRESUMEN
SBASE is a database of annotated protein domain sequences representing various structural, functional, ligand binding and topogenic segments of proteins. The current release of SBASE contains 27,211 entries which are provided with standardized names in order to facilitate retrieval. SBASE is cross-referenced to the major protein and nucleic acid databanks as well as to the PROSITE catalog of protein sequence patterns [Bairoch, A. (1992) Nucleic Acids Res., 20, Suppl., 2013-2118]. SBASE can be used to establish domain homologies through database search using programs such as FASTA [Lipman and Pearson (1985) Science, 227, 1436-1441], FASTDB [Brutlag et al. (1990) Comp. Appl. Biosci., 6, 237-245] or BLAST3 [Altschul and Lipman (1990) Proc. Natl. Acad. Sci. USA, 87, 5509-5513], which is especially useful in the case of loosely defined domain types for which efficient consensus patterns cannot be established. The use of SBASE is illustrated on the DNA binding protein Brain-4. The database and a set of search and retrieval tools are freely available on request to the authors or by anonymous 'ftp' file transfer from < ftp.icgeb.trieste.it >.
Asunto(s)
Bases de Datos Factuales , Proteínas/química , Secuencia de Aminoácidos , Proteínas de Unión al ADN/química , Genes Homeobox , Almacenamiento y Recuperación de la Información , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/química , Fragmentos de Péptidos/química , Homología de Secuencia , Programas InformáticosRESUMEN
Protein sequences are often derived by translating genetic information, rather than by classical protein sequencing. At the DNA level cysteines and half cystines are indistinguishable. Here we show that the sequential environments of 'free' cysteine and half cystine are different. A possible origin of this difference is discussed and a simple method to predict cysteines and half cystines from the amino acid sequence is also presented.
Asunto(s)
Cisteína/química , Cistina/química , Disulfuros/metabolismo , Proteínas/química , Secuencia de AminoácidosRESUMEN
A novel and generally applicable method is described for the detection of homology in distantly related proteins using a new domain sequence database that contains over 20,000 protein sequence segments of known function. The use of the method is illustrated on distantly related domains shared by complement components C1S and C1R, calcium-dependent serine proteinase and bone morphogenetic protein 1. New homologies are shown between human adducin and the actin-binding domains of alfa-actinin and dystrophin.
Asunto(s)
Proteínas de Unión a Calmodulina/genética , Proteínas de Microfilamentos/genética , Alineación de Secuencia/métodos , Actinina/genética , Secuencia de Aminoácidos , Proteínas Sanguíneas/genética , Secuencia de Consenso , Bases de Datos Factuales , Toma de Decisiones Asistida por Computador , Distrofina/genética , Cómputos Matemáticos , Datos de Secuencia Molecular , Conformación Proteica , Homología de Secuencia de Aminoácido , Programas InformáticosRESUMEN
The replaceability of amino acids as reflected in their neighbourhood selectivity is analyzed in this paper. Neighbourhood selectivity was found to be more characteristic of the individual amino acids than the other commonly used parameters. The residue replacement rank obtained was compared with other proposed ranks and was tested on naturally accepted point mutations in homologous proteins.
Asunto(s)
Diseño de Fármacos , Proteínas/química , Secuencia de Aminoácidos , Aminoácidos/química , Datos de Secuencia Molecular , Estructura Molecular , Mutagénesis Sitio-Dirigida , Mutación , Conformación Proteica , Proteínas/genéticaRESUMEN
In this paper the latest protein database consisting of more than a million amino acids is analyzed to characterize the short range regularities in the primary structure. The amino acid distributions along the polypeptide chain and among the proteins have been studied first. Their influence on the amino acid pair statistics was taken into account. We are primarily interested in the distances of the covalent structure, where the amino acid pair frequencies show non-random characters. The amino acid pairs separated by at least 20 residues in the covalent structure exhibit an exact Gaussian distribution. We found that there is a range of non-random pairing in the covalent structure. We conclude that the pair preference characters are different for each of the 20 x 20 amino acid pairs. The range of the non-random pairing varies from pair to pair, and in most cases it does not extend beyond the 9th neighbour. The preferences of a certain pair in a certain position can not be derived from the character of that pair in another position. The preference values of 400 amino acid pairs are listed for up to the pairs in 9th neighbour position. Some fields of potential application of these data have also been discussed.