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首页> 外文期刊>Biochemical Pharmacology >Identification and characterization of a novel protein histidine kinase in the islet beta cell: evidence for its regulation by mastoparan, an activator of G-proteins and insulin secretion.
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Identification and characterization of a novel protein histidine kinase in the islet beta cell: evidence for its regulation by mastoparan, an activator of G-proteins and insulin secretion.

机译：胰岛β细胞中一种新型蛋白质组氨酸激酶的鉴定和表征：其受G-蛋白和胰岛素分泌激活剂乳脂素调节的证据。

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Using insulin-secreting cells, we previously demonstrated that specific proteins associated with the cytosolic, secretory granule, and mitochondrial fractions undergo a novel type of phosphorylation on their histidine residues. Subsequently, we identified these proteins as the nucleoside diphosphate kinase (NDPK) [Kowluru and Metz, Biochemistry 1994;33:12495-503], the beta subunit of trimeric GTP-binding proteins [Kowluru et al., Biochem J 1996;313:97-107], and the alpha subunit of succinyl-CoA synthetase [Kowluru, Diabetologia 2001;44:89-94], respectively. Since several other enzymes of intermediary metabolism (e.g. ATP-citrate lyase and glucose-6-phosphatase) also undergo histidine phosphorylation, these initial findings may have a more generalized significance to beta cells. Herein, we characterized a novel protein histidine kinase in pancreatic beta cells, and determined it to be acid- and heat-labile as well as alkali-resistant in its phosphorylation of histone 4. Such an activity was detected in normal rat islets, human islets, and clonal beta (HIT-T15 and INS-1) cells, and could utilize either ATP or GTP as a phosphoryl donor (with K(m) values in the range of 60-100 microM). On a size-exclusion column, its molecular mass was estimated to be in the range of 60-70 kDa. It was stimulated by divalent cations (Mg(2+)>Mn(2+)>control=Ca(2+)=Zn(2+)=Co(2+)), but was resistant to polyamines. It was inactivated by known in vitro inhibitors of protein histidine phosphorylation (e.g. UDP or cromoglycate). Mastoparan, a global activator of G-proteins and insulin secretion from isolated beta cells, but not mastoparan-17, its inactive analog, stimulated histidine kinase activity and histidine phosphorylation of G(beta) subunit and insulin secretion from isolated rat islets. These studies identify, for the first time, a protein kinase activity in the pancreatic beta cell that does not act on traditional -Ser, -Tyr, or -Thr residues. They also establish a possible link between histidine kinase activity and G(beta) phosphorylation in isolated beta cells.
机译：使用胰岛素分泌细胞，我们以前证明与胞质，分泌颗粒和线粒体级分相关的特定蛋白质在其组氨酸残基上发生新型磷酸化。随后，我们将这些蛋白质鉴定为核苷二磷酸激酶（NDPK）[Kowluru and Metz，Biochemistry 1994; 33：12495-503]，即三聚体GTP结合蛋白的β亚基[Kowluru等，Biochem J 1996; 313： 97-107]和琥珀酰-CoA合成酶的α亚基[Kowluru，Diabetologia 2001; 44：89-94]。由于其他几种中间代谢酶（例如ATP柠檬酸裂合酶和葡萄糖6磷酸酶）也经历了组氨酸磷酸化，因此这些初步发现可能对β细胞具有更普遍的意义。本文中，我们在胰腺β细胞中鉴定了一种新型蛋白质组氨酸激酶，并确定其对组蛋白4的磷酸化具有酸和热不稳定性以及耐碱性。在正常大鼠胰岛，人胰岛中检测到这种活性。以及克隆性的β（HIT-T15和INS-1）细胞，并且可以利用ATP或GTP作为磷酰基供体（K（m）值在60-100 microM的范围内）。在尺寸排阻色谱柱上，其分子量估计为60-70 kDa。它被二价阳离子刺激（Mg（2 +）> Mn（2 +）>对照= Ca（2 +）= Zn（2 +）= Co（2+）），但对多胺具有抗性。它被已知的蛋白质组氨酸磷酸化的体外抑制剂（例如UDP或色甘酸）灭活。 Mastoparan是一种G蛋白的全球活化剂，可以从孤立的β细胞中分泌胰岛素，但不能激活其不活动的类似物mastoparan-17，它可以刺激组氨酸激酶的活性以及Gβ亚基的组氨酸磷酸化和大鼠胰岛中胰岛素的分泌。这些研究首次鉴定了胰腺β细胞中不作用于传统-Ser，-Tyr或-Thr残基的蛋白激酶活性。他们还在分离的β细胞中的组氨酸激酶活性和Gβ磷酸化之间建立了可能的联系。

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