Key Laboratory for Protein Sciences of Ministry of Education, School of Life Science, Tsinghua University, 100084, Beijing, P.R. China.
Beijing Advanced Innovation Center for Structural Biology & Beijing Frontier Research Center for Biological Structure, School of Life Science, Tsinghua University, 100084, Beijing, China.
Nat Commun. 2021 Jul 1;12(1):4057. doi: 10.1038/s41467-021-24320-4.
Chromatin remodeler ALC1 (amplification in liver cancer 1) is crucial for repairing damaged DNA. It is autoinhibited and activated by nucleosomal epitopes. However, the mechanisms by which ALC1 is regulated remain unclear. Here we report the crystal structure of human ALC1 and the cryoEM structure bound to the nucleosome. The structure shows the macro domain of ALC1 binds to lobe 2 of the ATPase motor, sequestering two elements for nucleosome recognition, explaining the autoinhibition mechanism of the enzyme. The H4 tail competes with the macro domain for lobe 2-binding, explaining the requirement for this nucleosomal epitope for ALC1 activation. A dual-arginine-anchor motif of ALC1 recognizes the acidic pocket of the nucleosome, which is critical for chromatin remodeling in vitro. Together, our findings illustrate the structures of ALC1 and shed light on its regulation mechanisms, paving the way for the discovery of drugs targeting ALC1 for the treatment of cancer.
染色质重塑因子 ALC1（肝癌扩增 1）对于修复受损 DNA 至关重要。它通过核小体表位被自动抑制和激活。然而，ALC1 的调控机制尚不清楚。本文报道了人源 ALC1 的晶体结构和与核小体结合的 cryoEM 结构。该结构显示，ALC1 的宏结构域与 ATP 酶马达的叶 2 结合，隔离两个核小体识别元件，解释了该酶的自动抑制机制。H4 尾巴与宏结构域竞争与叶 2 的结合，解释了该核小体表位对于 ALC1 激活的要求。ALC1 的双精氨酸锚定基序识别核小体的酸性口袋，这对于体外染色质重塑至关重要。总之，这些发现阐明了 ALC1 的结构及其调控机制，为发现针对 ALC1 的癌症治疗药物铺平了道路。
