Novel intermolecular zinc fingers and redox-driven conformational changes dictate tumor suppressor ZMYND11’s role in cooperative recognition of diverse targets

The zinc finger-myeloid-Nervy-DEAF-1 (ZMYND) protein family is associated with embryonic development and cancer regulation. Specifically, the tumor suppressor ZMYND11 is downregulated in multiple malignancies. Here, we identified an inhibitory role of ZMYND11 in colorectal cancers and determined crystal structures of the winged helix domain (WH), a plant homeodomain (PHD), coiled-coil-MYND (CC-MYND) domains, and their complex with an adenovirus E1A peptide. Unexpectedly, intermolecular zinc finger and intermolecular disulfide bonds were found for domains PHD and WH/CC-MYND, respectively. Interestingly, the oligomeric state of the PHD domain was pH-dependent, and the redox state of the CC domain impaired the binding, such as in the tumor or inflammatory microenvironments. Moreover, these conformational flexibilities facilitated ZMYND11 to bind diverse substrates. Comprehensive analysis and multiple assays showed that the Bromo-PWWP domains cooperate with the WH domain and the PHD domain to bind nucleic acids and histones, respectively. Thus, ZMYND11 is pivotal in chromatin binding and gene regulation, and may critically influence the expression of tumor-associated genes. Furthermore, both PHD and CC-MYND domains interact with the nucleic acid repair protein ALKBH6, revealing a previously uncharacterized epigenetic mechanism. Overall, these novel characteristics enable ZMYND11 as a global tumor suppressor to accommodate many substrates, thereby providing the structural basis for its broad recognition mechanisms.