Identification of a Novel Class of Farnesylation Targets by Structure-Based Modeling of Binding Specificity

Farnesylation is an important post-translational modification catalyzed by farnesyltransferase (FTase). Until recently it was believed that a C-terminal CaaX motif is required for farnesylation, but recent experiments have revealed larger substrate diversity. In this study, we propose a general structural modeling scheme to account for peptide binding specificity and recapitulate the experimentally derived selectivity profile of FTase in vitro. In addition to highly accurate recovery of known FTase targets, we also identify a range of novel potential targets in the human genome, including a new substrate class with an acidic C-terminal residue (CxxD/E). In vitro experiments verified farnesylation of 26/29 tested peptides, including both novel human targets, as well as peptides predicted to tightly bind FTase. This study extends the putative range of biological farnesylation substrates. Moreover, it suggests that the ability of a peptide to bind FTase is a main determinant for the farnesylation reaction. Finally, simple adaptation of our approach can contribute to more accurate and complete elucidation of peptide-mediated interactions and modifications in the cell

Defeitos congênitos no Município do Rio de Janeiro, Brasil: uma avaliação através do SINASC (2000-2004) Birth defects in Rio de Janeiro, Brazil: an evaluation through birth certificates (2000-2004)

Avaliou-se a ocorrência de defeitos congênitos em nascidos vivos no Município do Rio de Janeiro, Brasil, com base no Sistema de Informações sobre Nascidos Vivos (SINASC), no período de 1º de janeiro de 2000 a 31 de dezembro de 2004. Através de um estudo seccional e descritivo, estudaram-se as variáveis relativas aos defeitos congênitos (presença e aparelho ou sistema acometido), aos serviços de saúde, às mães, às gestações, aos recém-natos e aos partos. Constatou-se uma prevalência de defeitos congênitos de 83/10 mil nascidos vivos. Os sistemas orgânicos mais afetados foram o osteomuscular, nervoso central, genital, as fendas lábio-palatinas e as anomalias cromossômicas. A maioria dos casos nasceu nas maternidades municipais e na rede privada, e maior prevalência de defeitos congênitos ocorreu no Instituto Fernandes Figueira da Fundação Oswaldo Cruz. Os defeitos congênitos foram mais prevalentes entre os filhos de mulheres mais velhas e menos instruídas. O percentual de casos ignorados foi alto, chegando a 21% em algumas maternidades. Uma maior divulgação das informações do SINASC sobre defeitos congênitos deveria ser estimulada. Estudos de confiabilidade são recomendados para melhor aproveitamento das informações.<br>To evaluate the occurrence of birth defects in the city of Rio de Janeiro, Brazil, using the Live Birth Information System (SINASC), we performed a cross-sectional study on all live newborns with birth defects from January 1, 2000, to December 31, 2004. The variables referred to birth defects (presence and system affected), type of health service, mothers, gestations, live births, and deliveries. Prevalence of birth defects was 83/10,000 live births. The most frequent birth defects involved the musculoskeletal system, central nervous system, cleft lip and palate, and chromosomal anomalies. The majority of cases were born in public (municipal) and private maternity hospitals, with the highest prevalence in the Fernandes Figueira Insitute, Oswaldo Cruz Foundation. Older women and those with less schooling had more live born infants with birth defects. The proportion of reports with missing information was high, reaching 21% in some institutions. Wider dissemination of SINASC data on birth defects should be encouraged. Reliability studies are recommended for better use of these reports