Aging modulated by the Drosophila insulin receptor through distinct structure-defined mechanisms.
Aging modulated by the Drosophila insulin receptor through distinct structure-defined mechanisms.
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DOI：
10.1093/genetics/iyaa037
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发表时间：
2021-02-09
期刊：
影响因子：
3.3
通讯作者：
Tatar M
中科院分区：
文献类型：
--
作者：
Yamamoto R;Palmer M;Koski H;Curtis-Joseph N;Tatar M
果蝇胰岛素/IGF信号系统的突变减缓了衰老，同时也影响了生长和繁殖。为了理解这种多效性，我们在果蝇胰岛素受体InR中产生了一系列单密码子替换的等位基因。我们使用同源重组生成InR替换，并将每个替换与新兴的受体酪氨酸激酶结构和功能模型联系起来。当三个突变组合成反杂合子时，延长了寿命，同时延缓了生长和繁殖力。这些基因型降低了胰岛素刺激的Akt磷酸化，表明它们阻碍了激酶催化结构域的功能。在这些基因型中，寿命与产蛋量呈负相关，符合生活史权衡理论。相反，一个突变（InR353）位于激酶插入结构域，这是所有受体酪氨酸激酶中都存在的一个特征不明显的元件。值得注意的是，含有InR353的野生型杂合子在不影响生长或繁殖的情况下显著延长了寿命，并保留了完全磷酸化Akt的能力。果蝇胰岛素受体激酶插入结构域包含一个以前未被识别的SH2结合基序。我们提出激酶插入结构域与sh2相关的适配器蛋白相互作用，通过保持胰岛素敏感性和独立于生殖的机制影响衰老。
Mutations of the Drosophila melanogaster insulin/IGF signaling system slow aging, while also affecting growth and reproduction. To understand this pleiotropy, we produced an allelic series of single codon substitutions in the Drosophila insulin receptor, InR. We generated InR substitutions using homologous recombination and related each to emerging models of receptor tyrosine kinase structure and function. Three mutations when combined as trans-heterozygotes extended lifespan while retarding growth and fecundity. These genotypes reduced insulin-stimulated Akt phosphorylation, suggesting they impede kinase catalytic domain function. Among these genotypes, longevity was negatively correlated with egg production, consistent with life-history trade-off theory. In contrast, one mutation (InR353) was located in the kinase insert domain, a poorly characterized element found in all receptor tyrosine kinases. Remarkably, wild-type heterozygotes with InR353 robustly extended lifespan without affecting growth or reproduction and retained capacity to fully phosphorylate Akt. The Drosophila insulin receptor kinase insert domain contains a previously unrecognized SH2 binding motif. We propose the kinase insert domain interacts with SH2-associated adapter proteins to affect aging through mechanisms that retain insulin sensitivity and are independent of reproduction.
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