9EVE

Crystal structure of the ARM domain of human ZNFX1

Summary for 9EVE

• Entry DOI: 10.2210/pdb9eve/pdb
• Descriptor: NFX1-type zinc finger-containing protein 1 (1 entity in total)
• Functional Keywords: helicase, e3 ligase, armadillo domain, rna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 44926.08

Authors

Grabarczyk, D.B.,Deszcz, L.,Clausen, T. (deposition date: 2024-03-29, release date: 2025-04-09, Last modification date: 2025-10-29)

Primary citation

Grabarczyk, D.B.,Aird, E.J.,Reznikow, V.,Kirchgatterer, P.C.,Ehrmann, J.F.,Kurzbauer, R.,Bell, L.E.,Kellner, M.J.,Aggarwal, R.,Schleiffer, A.,Faas, V.,Deszcz, L.,Meinhart, A.,Versteeg, G.A.,Penninger, J.M.,Stelzl, L.S.,Gaidt, M.M.,Tessmer, I.,Corn, J.E.,Clausen, T.
A split-site E3 ligase mechanism enables ZNFX1 to ubiquitinate and cluster single-stranded RNA into ubiquitin-coated nucleoprotein particles.
Cell, 188:5995-, 2025

PubMed Abstract: Eukaryotic cells use a multi-layered immune response to combat intracellular pathogens. The ubiquitin ligase ZNFX1 has emerged as a crucial yet little understood player that regulates the immune response while protecting against RNA viruses. Our study unveils the molecular mechanism of ZNFX1, mediated by the joint activity of a helicase serving as a nucleic acid sensor and a non-conventional E3 module featuring a split active site. We demonstrate that single-stranded RNA stimulates E3 activity by fostering dimerization of ZNFX1 subunits that translocate along nucleic acid tracks. Juxtaposed E3 domains complement each other, leading to the ubiquitination of ZNFX1 itself and engaged RNA molecules, while clustering nucleic acids into dense nucleoprotein particles. We show that the E3 ligase activity of ZNFX1 protects cells during an immune response and propose that ubiquitin-coated particles formed by ZNFX1 represent part of an ancient mechanism to regulate both foreign and host RNA in the cell.

PubMed: 40876457
DOI: 10.1016/j.cell.2025.08.006

Experimental method

X-RAY DIFFRACTION (3.67 Å)