Cohesin catalyses the folding of the genome into loops that are anchored by CTCF¹. The molecular mechanism of how cohesin and CTCF structure the 3D genome has remained unclear. Here we show that a segment within the CTCF N terminus interacts with the SA2–SCC1 subunits of human cohesin. We report a crystal structure of SA2–SCC1 in complex with CTCF at a resolution of 2.7 Å, which reveals the molecular basis of the interaction. We demonstrate that this interaction is specifically required for CTCF-anchored loops and contributes to the positioning of cohesin at CTCF binding sites. A similar motif is present in a number of established and newly identified cohesin ligands, including the cohesin release factor WAPL^2,3. Our data suggest that CTCF enables the formation of chromatin loops by protecting cohesin against loop release. These results provide fundamental insights into the molecular mechanism that enables the dynamic regulation of chromatin folding by cohesin and CTCF.

粘连蛋白催化基因组折叠成由 CTCF ¹锚定的环。粘连蛋白和 CTCF 如何构建 3D 基因组的分子机制仍不清楚。在这里，我们展示了 CTCF N 末端内的一个片段与人粘连蛋白的 SA2-SCC1 亚基相互作用。我们以 2.7 Å 的分辨率报道了 SA2-SCC1 与 CTCF 复合物的晶体结构，揭示了相互作用的分子基础。我们证明这种相互作用是 CTCF 锚定环特别需要的，并且有助于粘连蛋白在 CTCF 结合位点的定位。类似的基序存在于许多已建立的和新鉴定的粘连蛋白配体中，包括粘连蛋白释放因子 WAPL ^2,3 。我们的数据表明，CTCF 通过保护粘连蛋白免于环释放来实现染色质环的形成。这些结果为通过粘连蛋白和 CTCF 动态调节染色质折叠的分子机制提供了基本见解。