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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Human G_(sα) mutant causes pseudohypoparathyroidism type Iaeonatal diarrhea, a potential cell-specific role of the palmitoylation cycle
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Human G_(sα) mutant causes pseudohypoparathyroidism type Iaeonatal diarrhea, a potential cell-specific role of the palmitoylation cycle

机译：人G_（sα）突变体导致假性甲状旁腺功能减退Ia型/新生儿腹泻，这可能是棕榈酰化周期的细胞特异性作用

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Pseudohypoparathyroidism type Ia (PHP-Ia) results from the loss of one allele of G_(sα), causing resistance to parathyroid hormone and other hormones that transduce signals via G_s. Most G_(sα)mutations cause the complete loss of protein expression, but some cause loss of function only, and these have provided valuable insights into the normal function of G proteins. Here we have analyzed a mutant G_(sα) (αs-AVDT) harboring AVDT amino acid repeats within its GDP/GTP binding site, which was identified in unique patients with PHP-la accompanied by neonatal diarrhea. Biochemical and intact cell analyses showed that as-AVDT is unstable but constitutively active as a result of rapid GDP release and reduced GTP hydrolysis. This instability underlies the PHP-Ia phenotype. αs-AVDT is predominantly localized in the cytosol, but in rat and mouse small intestine epithelial cells (IEC-6 and DIF-12 cells) as-AVDT was found to be localized predominantly in the membrane where adenylyl cyclase is present and constitutive increases in cAMP accumulation occur in parallel. The likely cause of this membrane localization is the inhibition of an activation-dependent decrease in as palmitoylation. Upon the overexpression of acyl-protein thioesterase 1, however, αs-AVDT translocates from the membrane to the cytosol, and the constitutive accumulation of cAMP becomes attenuated. These results suggest that PHP-Ia results from the instability of αs-AVDT and that the accompanying neonatal diarrhea may result from its enhanced constitutive activity in the intestine. Hence, palmitoylation may control the activity and localization of G_(sα) in a cell-specific manner.
机译：假性甲状旁腺功能减退症Ia型（PHP-Ia）由G_（sα）的一个等位基因的丢失导致，导致对甲状旁腺激素和其他通过G_s传递信号的激素产生抗性。大多数G_（sα）突变会导致蛋白质表达的完全丧失，但有些会仅导致功能丧失，这些为G蛋白的正常功能提供了有价值的见解。在这里，我们分析了一个突变体G_（sα）（αs-AVDT），在其GDP / GTP结合位点内具有AVDT氨基酸重复序列，该突变体是在PHP-la伴有新生儿腹泻的独特患者中发现的。生化和完整细胞分析表明，由于GDP快速释放和GTP水解减少，as-AVDT不稳定，但具有组成性活性。这种不稳定性是PHP-1a表型的基础。 αs-AVDT主要位于细胞质中，但在大鼠和小鼠的小肠上皮细胞（IEC-6和DIF-12细胞）中，as-AVDT主要位于存在腺苷酸环化酶的膜中，而组成成分增加cAMP累积并行发生。这种膜定位的可能原因是抑制了棕榈酰化过程中激活依赖性降低。但是，在酰基蛋白硫酯酶1过表达后，αs-AVDT从膜转移到细胞质中，而cAMP的组成性积累减弱。这些结果表明，PHP-Ia是由αs-AVDT的不稳定性引起的，伴随的新生儿腹泻可能是由于其在肠中的组成活性增强所致。因此，棕榈酰化可以以细胞特异性方式控制G_（sα）的活性和定位。

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