9R4I

An auto inhibitory loop in the MiDAC histone deacetylase complex

Summary for 9R4I

• Entry DOI: 10.2210/pdb9r4i/pdb
• EMDB information: 53567
• Descriptor: Histone deacetylase 1, Mitotic deacetylase-associated SANT domain protein, Deoxynucleotidyltransferase terminal-interacting protein 1, ... (6 entities in total)
• Functional Keywords: hdac1 dnttip1 mideas histone deacetylase complex, gene regulation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 244651.09

Authors

Fairall, L.,Schwabe, J.W.R. (deposition date: 2025-05-07, release date: 2026-02-25)

Primary citation

Fairall, L.,Sirvydis, K.,Turnbull, R.E.,Knottnerus, S.J.,Gonchar, O.,Muskett, F.W.,Jukes-Jones, R.,van Brussel, L.,van de Geer, E.,van Gassen, K.,Badenhorst, P.,Johnson, D.,Terhal, P.A.,van Hasselt, P.M.,van Jaarsveld, R.H.,Schwabe, J.W.
A de novo missense variant in MIDEAS results in increased deacetylase activity of the MiDAC HDAC complex causing a neurodevelopmental syndrome.
Nat Commun, 16:10472-10472, 2025

PubMed Abstract: MIDEAS is a scaffold protein that, together with DNTTIP1, mediates assembly of the MiDAC histone deacetylase complex. Mice lacking MiDAC die before birth suggesting a key developmental function. Here, we report two unrelated individuals, with a multisystem disorder characterised by delayed speech development, joint contractures, dysmorphic features and dysmotility of the gut. Both individuals have the same de novo heterozygous missense variant in MIDEAS (p.Tyr654Ser). A cryoEM structure of the MiDAC complex reveals that this amino acid is located in a conserved auto-inhibitory loop that covers the active site of the deacetylase enzyme. We suggest that the variant results in loop displacement leading to elevated deacetylase activity. In support, we observe reciprocal gene expression changes in patient fibroblasts compared with a cell line following rapid MiDAC degradation. Our results establish MIDEAS as a dominant monogenic disease gene and that hyperactivity of the MiDAC complex results in a characteristic multisystem disorder.

PubMed: 41290615
DOI: 10.1038/s41467-025-65472-x

Experimental method

ELECTRON MICROSCOPY (2.92 Å)