Vacuolar protein sorting-associated protein 72–Histone H2A.Z protein–protein interface (VPS72–H2A.Z interface)

The Vacuolar protein sorting-associated protein 72 (VPS72), also known as YL1, is a dedicated histone chaperone responsible for the site-specific deposition of the histone variant H2A.Z into chromatin (UniProt Q15906). This protein-protein interface involves the binding of the VPS72 C-terminal domain to the H2A.Z-H2B heterodimer, facilitating its incorporation into nucleosomes via the SRCAP and p400/TIP60 remodeling complexes (Liang et al., 2016, Nature). The exchange of canonical H2A for H2A.Z is a fundamental epigenetic mechanism that regulates promoter accessibility, transcriptional activation, and the DNA damage response (Latrick et al., 2016, Nat Struct Mol Biol). In various cancers, including breast, prostate, and melanoma, the VPS72–H2A.Z axis is frequently upregulated, driving oncogenic gene expression and contributing to therapeutic resistance (Vardabasso et al., 2015, Nat Commun). Targeting this specific interface offers a strategy to selectively inhibit H2A.Z-mediated pathways without affecting global histone dynamics. While no clinical drugs currently target this interface, experimental approaches using peptidomimetics and small-molecule screens are being explored to disrupt this interaction for cancer therapy.

Other names

YL1–H2A.Z interfaceVPS72–H2AFZ interfaceYL1–H2AFZ protein-protein interactionVPS72–H2A.Z-H2B complex interface

Inhibition of H2A.Z deposition into chromatin by competitively disrupting the chaperone-histone binding interface