9Z04

Structure of human lymphoid-specific helicase HELLS in its auto-inhibitory state

Summary for 9Z04

• Entry DOI: 10.2210/pdb9z04/pdb
• EMDB information: 73693
• Descriptor: Lymphoid-specific helicase (1 entity in total)
• Functional Keywords: lymphoid-specific helicase, sf2 chromatin remodeler, icf syndrome, atp-binding, chromatin-binding, dna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 583307.95

Authors

Kaur, G.,Horton, J.R.,Cheng, X. (deposition date: 2025-10-31, release date: 2026-04-29)

Primary citation

Kaur, G.,Ren, R.,Lee, J.,Horton, J.R.,Zhang, X.,Gao, Y.,Chen, T.,Cheng, X.
Structure of human lymphoid-specific helicase HELLS in its autoinhibited state.
Nucleic Acids Res., 54:-, 2026

PubMed Abstract: Helicase, Lymphoid Specific (HELLS), also known as Lymphoid-Specific Helicase (LSH), is a member of the SNF2 chromatin-remodeling family that regulates DNA methylation and heterochromatin organization. Unlike most chromatin remodelers, HELLS is catalytically inactive in its apo form and requires the DNA-binding protein CDCA7 for activation, though the underlying mechanism has remained unclear. Here, we combine biochemical, biophysical, and cryo-electron microscopy analyses to define the structural basis of HELLS autoinhibition. HELLS alone assembles into a hexameric (trimer of dimers) architecture stabilized by interactions between its N-terminal coiled-coil (CC) domain and ATPase Lobe-1, while ATPase Lobe-2 remains flexible and disengaged. The CC domain functions both as an oligomerization scaffold and as an autoinhibitory module that restricts catalytic activity. Binding of CDCA7 and DNA promotes formation of an active HELLS-CDCA7-DNA ternary complex. CDCA7 recognizes hemimethylated CpG dinucleotides in both B-form and non-B-form DNA and stimulates HELLS ATPase activity. Together, these findings reveal the mechanism of HELLS autoinhibition and its activation by CDCA7 and DNA, providing new insight into how the HELLS-CDCA7-DNA ternary complex maintains DNA methylation and heterochromatin integrity.

PubMed: 41954988
DOI: 10.1093/nar/gkag326

Experimental method

ELECTRON MICROSCOPY (2.99 Å)