Integrative Structural Modeling of Intrinsically Disordered Regions in a Human HDAC2 Chromatin Remodeling Complex

Abstract Histone deacetylase-containing complexes play central roles in chromatin regulation, yet the structural organization of their intrinsically disordered regions (IDRs) remains poorly understood. Here, we identify the previously uncharacterized protein C16orf87, which we renamed MHAP1, as a binding partner of HDAC2 and MIER1. Because all three proteins contain extensive IDRs that remain difficult to study using single structural analysis methods, we employed an integrative structural approach combining cross-linking mass spectrometry (XL-MS) with integrative structural modeling to define the architecture of the complex. The resulting integrative structural model reveals that the previously uncharacterized C-terminal IDR of HDAC2 acts as a key interaction hub, engaging both the ELM2 domain of MIER1 and the N- and C-terminal regions of MHAP1. These findings provide the first structural framework for the interactions among HDAC2:MIER1:MHAP1 and demonstrate how intrinsically disordered regions can mediate assembly of a chromatin-associated deacetylase complex. Finally, this research further demonstrates the ability of XL-MS to facilitate integrative structural modeling of protein complexes. Mass spectrometry data may be accessed through ProteomeXchange via PXD082280 and the MassIVE repository MSV000102752.