RESUMO
The family of genes encoding T-cell immunoglobulin and mucin-domain containing proteins (Tim), which are cell-surface molecules expressed in CD4(+) T helper cells, has important roles in the immune system. Here, we report three unusual patterns of genetic variation in the human hepatitis A virus cellular receptor 1 gene (HAVCR1) that are similar to patterns observed in major histocompatibility complex loci. First, levels of polymorphism in exon 4 of HAVCR1 were exceptionally high in humans (nucleotide diversity (pi)=45.45 x 10(-4)). Second, nonsynonymous substitutions and insertion/deletion variants were more frequent than synonymous substitutions in that exon (10 out of 12 variants). The rate of the mean number of nucleotide substitutions at nonsynonymous sites to synonymous sites at HAVCR1-exon 4 is >1 (P(A)/P(S)=1.92 and pi(A)/pi(S)=2.23). Third, levels of divergence among human, chimp, and gorilla sequences were unusually high in HAVCR1-exon 4 sequences. These features suggest that patterns of variation in HAVCR1 have been shaped by both positive and balancing natural selection in the course of primate evolution. Evidence that the effects of natural selection are largely restricted to the mucin domain of HAVCR1 suggests that this region may be of particular evolutionary and epidemiological interest.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Éxons/genética , Variação Genética , Glicoproteínas de Membrana/genética , Filogenia , Receptores Virais/genética , Seleção Genética , Sequência de Bases , Éxons/fisiologia , Receptor Celular 1 do Vírus da Hepatite A , Humanos , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/fisiologia , Glicoproteínas de Membrana/metabolismo , Dados de Sequência Molecular , Mucinas/genética , Estrutura Terciária de Proteína/genética , Estrutura Terciária de Proteína/fisiologia , Receptores Virais/metabolismoRESUMO
A 25.6 kb region at chromosome 5q31, covering the entire human interleukin 13 (IL-13) and interleukin 4 (IL-4) genes, has been reported to be associated with bronchial asthma. We have examined nucleotide variations at this locus in African, European American, and Japanese populations, using 120 diallelic variants. A block of strong linkage disequilibrium (LD) (mid R:D'mid R:>0.7) spans a 10 kb region containing IL-4 in European American and Japanese populations, and is present but less clear in African samples. Two major haplotypes at IL-4 account for >80% of haplotypes in European Americans and Japanese. These haplotypes are common and quite diverged from each other and the ancestral haplotype, resulting in highly significant deviations from neutrality. F(ST) statistics show that European American and Japanese populations are unusually distinct at the IL-4 locus. The most common haplotype in the European American population is much less common in the Japanese population, and vice versa. This implies that natural selection has acted on IL-4 haplotypes differently in different populations. This selected variation at IL-4 may account for some genetic variance underlying susceptibility to asthma and other allergic diseases. The strong LD observed in the IL-4 region may allow more efficient disease-association studies using this locus.
Assuntos
Hipersensibilidade/genética , Interleucina-13/genética , Interleucina-4/genética , Polimorfismo de Nucleotídeo Único , Adaptação Fisiológica/genética , Etnicidade/genética , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Haplótipos/genética , Humanos , Hipersensibilidade/etnologia , Desequilíbrio de Ligação/genética , Grupos Raciais/genéticaRESUMO
Metabotropic glutamate receptors, which are members of a G protein-coupled receptor family, mediate the glutamate responses by coupling to the intracellular signal transduction pathway. We herein report that calmodulin (CaM) interacts with the metabotropic glutamate receptor subtype 5 (mGluR5) in a Ca2+-dependent manner in vitro. CaM is capable of binding on two distinct sites in the COOH-terminal intracellular region of the receptor with different affinities. The CaM binding domains are separated by an alternatively spliced exon cassette present in one of the splicing isoforms of mGluR5. By using fusion proteins and synthetic peptides we showed that protein kinase C phosphorylates both CaM binding regions. This phosphorylation is inhibited by the binding of CaM to the receptor, and conversely the binding is inhibited by the phosphorylation. These antagonisms of the CaM binding and phosphorylation thus suggest the possibility that they regulate the receptor responses in vivo.
Assuntos
Calmodulina/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Sequência de Aminoácidos , Animais , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Fosforilação , Proteína Quinase C/metabolismo , Receptor de Glutamato Metabotrópico 5 , Proteínas Recombinantes de Fusão/metabolismo , Células Tumorais CultivadasRESUMO
A thin-layer chromatographic method was investigated in which two series of sodium alkanesulphonates (C4-C18) and alkylbenzenesulphonates (C0-C14) were separated. All of the compounds tested were clearly separated on polyamide layers with aqueous ammonia-pyridine and aqueous ammonia-pyridine-methanol systems and detected with high sensitivity by spraying with a pynacryptol yellow reagent and then observing under UV light (253.6nm).
