Elias Maria, Gani Samar, Lerner Yana, Yamin Katreen, Tor Chen, Patel Adarsh, Matityahu Avi, Dessau Moshe, Qvit Nir, Onn Itay
Chromosome Instability and Dynamics Lab, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
Protein-Protein Interactions Lab, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
iScience. 2023 Jul 28;26(9):107498. doi: 10.1016/j.isci.2023.107498. eCollection 2023 Sep 15.
Cohesin mediates the 3-D structure of chromatin and is involved in maintaining genome stability and function. The cohesin core comprises Smc1 and Smc3, elongated-shaped proteins that dimerize through globular domains at their edges, called head and hinge. ATP binding to the Smc heads induces their dimerization and the formation of two active sites, while ATP hydrolysis results in head disengagement. This ATPase cycle is essential for driving cohesin activity. We report on the development of the first cohesin-inhibiting peptide (CIP). The CIP binds Smc3 and inhibits the ATPase activity of the holocomplex. Treating yeast cells with the CIP prevents cohesin's tethering activity and, interestingly, leads to the accumulation of cohesin on chromatin. CIP3 also affects cohesin activity in human cells. Altogether, we demonstrate the power of peptides to inhibit cohesin in cells and discuss the potential application of CIPs as a therapeutic approach.
黏连蛋白介导染色质的三维结构，并参与维持基因组的稳定性和功能。黏连蛋白核心由Smc1和Smc3组成，它们是细长形蛋白质，通过其边缘的球状结构域二聚化，这些球状结构域称为头部和铰链区。ATP与Smc头部结合会诱导其二聚化并形成两个活性位点，而ATP水解则导致头部脱离。这种ATP酶循环对于驱动黏连蛋白活性至关重要。我们报告了首个黏连蛋白抑制肽（CIP）的研发情况。该CIP结合Smc3并抑制全复合物的ATP酶活性。用CIP处理酵母细胞可阻止黏连蛋白的拴系活性，有趣的是，还会导致黏连蛋白在染色质上的积累。CIP3在人类细胞中也会影响黏连蛋白活性。总之，我们展示了肽在细胞中抑制黏连蛋白的能力，并讨论了CIP作为一种治疗方法的潜在应用。
