Multicomplex Integrative Structural Modeling of a Human Histone Deacetylase Interactome

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Histone Deacetylase (HDAC) 1 and 2 are crucial enzymes in chromatin remodeling complexes like NuRD, SIN3, and CoREST.
• HDAC1/2 possess intrinsically disordered regions (IDRs) in their C-terminal domains (CTDs), whose structures and assembly roles are unclear.

Purpose of the Study:

• To elucidate the structural assembly of HDAC1/2 within chromatin remodeling complexes.
• To investigate the structural behavior of the CTD IDR in HDAC1/2.

Main Methods:

• Utilized crosslinking mass spectrometry (XL-MS) and the Integrative Modeling Platform to map protein interaction networks and build complex models.
• Employed an AlphaFold-enabled XL-MS constrained modeling approach to determine HDAC1 assembly.
• Developed integrative structural models for NuRD, SIN3A, and CoREST complexes, including a detailed NuRD subcomplex model.

Main Results:

• Successfully modeled the structures of NuRD, SIN3A, and CoREST complexes.
• Demonstrated that the CTD IDR of HDAC1 folds into alpha helices upon complex assembly.
• Generated a comprehensive structural model of a NuRD subcomplex comprising six IDRs.

Conclusions:

• The study provides novel structural insights into HDAC1/2 complex assembly and the role of IDRs.
• The integrative modeling approaches are broadly applicable for studying complex protein interactions and IDRs.