Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1.
Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1.
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DOI：
10.1016/j.jbc.2021.100837
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Goult BT
中科院分区：
文献类型：
--
作者：
Gough RE;Jones MC;Zacharchenko T;Le S;Yu M;Jacquemet G;Muench SP;Yan J;Humphries JD;Jørgensen C;Humphries MJ;Goult BT
Talin（TLN 1）是粘附复合物的机械敏感组分，其直接将整合素偶联到肌动蛋白细胞骨架。在对力的反应中，talin经历了其多个杆结构域的开关样行为，这些杆结构域调节与其结合伴侣的相互作用。细胞周期蛋白依赖性激酶-1（CDK 1）是细胞周期的关键调节因子，通过大量蛋白质靶点的同步磷酸化发挥其作用。CDK 1活性在间期期间维持粘附，并且其抑制是成功有丝分裂所需的细胞形状和粘附的紧密编排变化的先决条件。使用生物化学，结构和细胞生物学的方法相结合，我们证明了塔林和CDK 1之间的直接相互作用，发生在网站的整合素介导的粘附。突变证实CDK 1含有一个功能性的talin结合LD基序，并且talin内的结合位点被精确定位到螺旋束R8。Talin还含有以S1589为中心的共有CDK 1磷酸化基序，该位点在体外被CDK 1磷酸化。一个磷酸模拟突变体的这个网站内塔林降低了细胞骨架适配器KANK的结合亲和力，并削弱了该地区的反应，以单分子拉伸测量力，可能改变下游mechanotransductionpathways。主细胞周期调节因子CDK 1与主要整联蛋白效应因子talin的直接结合代表了细胞增殖和细胞粘附机制的偶联，从而表明了微环境可以控制多细胞生物体中细胞分裂的机制。
Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms.
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