Journal article
The schizophrenia associated protein DISC1 forms a multivalent tetrameric hub via conserved UVR dimers
- 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 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
-
-
(Preview, Accepted manuscript, pdf, 73.1MB, Terms of use)
-
- Publisher copy:
- 10.1038/s41467-026-71838-6
Authors
+ Wellcome Trust
More from this funder
- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 202827/Z/16/Z
- 226647/Z/22/Z
+ UK Research and Innovation
More from this funder
- Funder identifier:
- https://ror.org/001aqnf71
- Grant:
- EP/X025713/1
+ Engineering and Physical Sciences Research Council
More from this funder
- Funder identifier:
- https://ror.org/0439y7842
- Grant:
- EP/T03419X/1
- Publisher:
- Nature Research
- Journal:
- Nature Communications More from this journal
- Place of publication:
- England
- Publication date:
- 2026-04-17
- Acceptance date:
- 2026-03-30
- DOI:
- EISSN:
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2041-1723
- Pmid:
-
41997921
- Language:
-
English
- Pubs id:
-
2408281
- Local pid:
-
pubs:2408281
- Source identifiers:
-
W7154597193
- Deposit date:
-
2026-05-11
- ARK identifier:
Terms of use
- Copyright holder:
- Zhou et al.
- Copyright date:
- 2026
- Rights statement:
- © The Author(s) 2026. Open Access, This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Notes:
- This is the accepted manuscript version of the article. The final version is forthcoming from Nature Research at https://dx.doi.org/10.1038/s41467-026-71838-6
- Licence:
- CC Attribution (CC BY)
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