A new layer of phosphoinositide-mediated allosteric regulation uncovered for SHIP2
A new layer of phosphoinositide-mediated allosteric regulation uncovered for SHIP2
复制标题
DOI：
10.1096/fj.202100561r
复制
发表时间：
2021-08-01
期刊：
影响因子：
4.8
通讯作者：
Lietha, Daniel
中科院分区：
文献类型：
--
作者：
Le Coq, Johanne;Lopez Navajas, Pilar;Lietha, Daniel
含有肌醇5-磷酸酶2的Src同源物2(SHIP2)是一个大的多结构域酶，催化磷脂磷脂酰肌醇3，4，5-三磷酸(PI(3，4，5)P-3)脱磷生成PI(3，4)P-2。PI(3，4，5)P-3是一个关键的脂质第二信使，控制信号蛋白向质膜的募集，从而调节大量的细胞事件，包括增殖、生长、凋亡和细胞骨架重排。SHIP2与PI3K和PTEN一起调节质膜上PI(3，4，5)P-3的水平，与癌症和2型糖尿病等严重疾病密切相关；然而，其调控机制的许多方面仍不清楚。我们最近报道了SHIP2 C2结构域的激活效应，在这里我们描述了通过Pleckstrin同源相关(PHR)结构域进行额外的一层调节。我们显示了磷脂酰肌醇诱导的向高活性状态的酶的转变，使磷酸酶活性增加了10-15倍。我们进一步证明了PI(3，4)P-2直接与PHR结构域相互作用，从而触发这种变构激活。对SHIP2膜上的PHR-磷酸酶-C2区域的模拟表明，与PHR结构域没有主要的域间相互作用，但两个连接子之间的密切接触提供了一条可能的变构通讯途径。总之，我们的数据表明，PHR结构域作为一个变构模块，调节SHIP2的催化活性，以响应细胞膜中特定的磷脂酰肌醇水平。
The Src homology 2 containing inositol 5-phosphatase 2 (SHIP2) is a large multidomain enzyme that catalyzes the dephosphorylation of the phospholipid phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P-3) to form PI(3,4)P-2. PI(3,4,5)P-3 is a key lipid second messenger controlling the recruitment of signaling proteins to the plasma membrane, thereby regulating a plethora of cellular events, including proliferation, growth, apoptosis, and cytoskeletal rearrangements. SHIP2, alongside PI3K and PTEN, regulates PI(3,4,5)P-3 levels at the plasma membrane and has been heavily implicated in serious diseases such as cancer and type 2 diabetes; however, many aspects of its regulation mechanism remain elusive. We recently reported an activating effect of the SHIP2 C2 domain and here we describe an additional layer of regulation via the pleckstrin homology-related (PHR) domain. We show a phosphoinositide-induced transition to a high activity state of the enzyme that increases phosphatase activity up to 10-15 fold. We further show that PI(3,4)P-2 directly interacts with the PHR domain to trigger this allosteric activation. Modeling of the PHR-phosphatase-C2 region of SHIP2 on the membrane suggests no major inter-domain interactions with the PHR domain, but close contacts between the two linkers offer a possible path of allosteric communication. Together, our data show that the PHR domain acts as an allosteric module regulating the catalytic activity of SHIP2 in response to specific phosphoinositide levels in the cell membrane.