Phospholipase C gamma 2 (PLCĪ³2) plays important roles in cell signaling downstream of various membrane receptors. PLCĪ³2 contains a multidomain inhibitory region critical for its regulation, while it h Show more
Phospholipase C gamma 2 (PLCĪ³2) plays important roles in cell signaling downstream of various membrane receptors. PLCĪ³2 contains a multidomain inhibitory region critical for its regulation, while it has remained unclear how these domains contribute to PLCĪ³2 activity modulation. Here we determined three structures of human PLCĪ³2 in autoinhibited states, which reveal dynamic interactions at the autoinhibition interface, involving the conformational flexibility of the Src homology 3 (SH3) domain in the inhibitory region, and its previously unknown interaction with a carboxyl-terminal helical domain in the core region. We also determined a structure of PLCĪ³2 bound to the kinase domain of fibroblast growth factor receptor 1 (FGFR1), which demonstrates the recognition of FGFR1 by the nSH2 domain in the inhibitory region of PLCĪ³2. Our results provide structural insights into PLCĪ³2 regulation that will facilitate future mechanistic studies to understand the entire activation process. Show less
Apolipoprotein A5 (APOA5) gene polymorphisms are usually associated with plasma triglyceride levels. We evaluated the relationship of the APOA5 -1131T>C and c.56C>G polymorphisms [single nucleotide po Show more
Apolipoprotein A5 (APOA5) gene polymorphisms are usually associated with plasma triglyceride levels. We evaluated the relationship of the APOA5 -1131T>C and c.56C>G polymorphisms [single nucleotide polymorphism (SNP)] with serum lipids, dyslipidemia [low high-density lipoprotein (HDL)/high triglyceride] and the risk for metabolic syndrome (MS) in the Turkish Adult Risk Factor study. We genotyped SNPs using the Taqman allelic discrimination assays in 1564 Turkish adults (51.4% female, mean age 54.1+/-11.6 years). MS and dyslipidemia were defined using the criteria of the National Cholesterol Education Program. For both SNPs, rare allele carriers had significantly higher fasting triglyceride levels in both genders, except the c.56G allele in men. The -1131C allele was associated with lower HDL cholesterol (HDL-C) levels in women. In relation to dyslipidemia, the c.56C>G and haplotype 1 had significant gender-genotype interactions (p<0.05). Otherwise, both SNPs were significantly associated with dyslipidemia after adjustment for risk factors in women. After similar adjustment, non-carriers of the haplotype 1 (odds ratio=4.1, p=0.003) increased the MS risk in women. However, no significant associations emerged between SNPs and HDL-C, dyslipidemia or MS in a similar analysis in men. Excess risk for low HDL-C, dyslipidemia and MS is associated with the rare alleles of the APOA5 SNPs and non-carriers of common haplotype in women. Show less