• ATRX ADD domain specifically binds macroH2A histone-fold domain, not canonical H2A, via a D/E-rich loop and L12 loop interaction.
• ATRXADD uses a conserved interface to recognize both macroH2A and H3, leading to competitive binding between these histones.
• NuRD complex components are identified as potential ATRXADD-associating proteins, with CDH4 directly interacting with ATRXADD by mimicking H3.
• These findings reveal the versatility of ATRXADD in recognizing diverse chromatin regulators, providing insights into ATRX's roles in epigenetic regulation and pathogenesis.