Chromosome Segregation Laboratory, The Francis Crick Institute, London, United Kingdom.
Mechanobiology and Biophysics Laboratory, The Francis Crick Institute, London, United Kingdom.
Elife. 2021 Jul 26;10:e67530. doi: 10.7554/eLife.67530.
The cohesin complex topologically encircles DNA to promote sister chromatid cohesion. Alternatively, cohesin extrudes DNA loops, thought to reflect chromatin domain formation. Here, we propose a structure-based model explaining both activities. ATP and DNA binding promote cohesin conformational changes that guide DNA through a kleisin N-gate into a DNA gripping state. Two HEAT-repeat DNA binding modules, associated with cohesin's heads and hinge, are now juxtaposed. Gripping state disassembly, following ATP hydrolysis, triggers unidirectional hinge module movement, which completes topological DNA entry by directing DNA through the ATPase head gate. If head gate passage fails, hinge module motion creates a Brownian ratchet that, instead, drives loop extrusion. Molecular-mechanical simulations of gripping state formation and resolution cycles recapitulate experimentally observed DNA loop extrusion characteristics. Our model extends to asymmetric and symmetric loop extrusion, as well as z-loop formation. Loop extrusion by biased Brownian motion has important implications for chromosomal cohesin function.
黏合蛋白复合物通过拓扑缠绕 DNA 以促进姐妹染色单体黏合。另外,黏合蛋白也会向外推出 DNA 环,这些 DNA 环被认为反映了染色质结构域的形成。在这里,我们提出了一个基于结构的模型,该模型可以解释这两种活性。ATP 和 DNA 结合会促进黏合蛋白构象发生变化,使 DNA 通过 kleisin N 门进入 DNA 夹持状态。两个 HEAT 重复 DNA 结合模块与黏合蛋白的头部和铰链相关联,现在并列在一起。ATP 水解后,夹持状态的解体会触发铰链模块的单向运动,通过将 DNA 穿过 ATP 酶头部门来完成拓扑 DNA 的进入。如果头部门的通过失败,铰链模块的运动就会产生布朗棘轮,从而驱动 DNA 环的外推。夹持状态形成和解析循环的分子力学模拟再现了实验观察到的 DNA 环外推特征。我们的模型扩展到了不对称和对称的环外推以及 z 环的形成。通过有偏布朗运动的环外推对染色体黏合蛋白的功能具有重要意义。