The R203W substitution drives PACS-1 syndrome by disrupting intramolecular regulation.

The c607C>T mutation in the PACS1 gene results in an Arg203Trp substitution in the multifunctional protein PACS-1, and drives a syndrome characterized by intellectual disability, seizures, craniofacial dysmorphisms, and various characteristics of the autism spectrum. On the molecular level, this syndrome, in part, results from enhanced association of PACS-1 with the protein deacetylase HDAC6. PACS-1 uses its Furin binding region (FBR: amino acids 101-273) to directly interact with the catalytic domains of HDAC6. We present the solution structure of a chimeric PACS-1 FBR and use NMR to demonstrate that the PACS-1/HDAC6 interaction is regulated by an intramolecular mechanism involving the central unstructured region of PACS-1 folding back across the FBR and engaging in contacts with an extended, positively charged loop. The R203W substitution, located in this loop, disrupts this regulatory interaction and, in vitro, displays the ability to promote aberrant protein-protein interactions.