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-Structure paper
| Title | The schizophrenia associated protein DISC1 forms a multivalent tetrameric hub via conserved UVR dimers. |
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| Journal, issue, pages | Nat Commun, Vol. 17, Issue 1, Year 2026 |
| Publish date | Apr 17, 2026 |
 Authors | Jin Chuan Zhou / Jiri Kratochvil / Fei Ye / Kamel El Omari / Philipp Kukura / Mingjie Zhang / Elena Seiradake /   |
| PubMed Abstract | DISC1 is a pleiotropic protein with essential roles in neuronal proliferation and migration, intracellular signalling and cargo transport. It associates with a diverse array of partner molecules in ...DISC1 is a pleiotropic protein with essential roles in neuronal proliferation and migration, intracellular signalling and cargo transport. It associates with a diverse array of partner molecules in these contexts. Mutations at the DISC1 locus are strongly associated with a spectrum of mental illnesses such as schizophrenia and depression. Despite its clinical relevance, the molecular architecture and function of DISC1 have remained largely elusive. We present a cryo-EM structure of the entire conserved core region of DISC1. The structure reveals an intricate homotetrameric assembly that harbours conserved bacteria-derived UVR domains. Four of these domains, one from each monomer, mediate extensive contacts forming two asymmetric dimer units. The dimers in turn interface with each other at two distinct coiled coil domains to achieve a two-fold symmetric tetramer. Mutational analysis shows that this tetrameric architecture enables DISC1 to simultaneously bind multiple copies of NDE1 client protein. Importantly, tetramerization and partner binding are structurally independent functions of DISC1. Altogether, our study provides a compelling molecular model of an ancient bacteria protein fold participating in the assembly of a multivalent mammalian scaffold hub that can coordinate multiple partner molecules. |
 External links | Nat Commun / PubMed:41997921 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.9 Å |
| Structure data | EMDB-54277, PDB-9rux: |
| Source |
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 Keywords | STRUCTURAL PROTEIN / Scaffold / complex / tetramer / coiled coil / UVR domain / psychiatric disorder |
mus musculus (house mouse)