ArticleThe Journal of biological chemistry2013
SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 55 citations in OpenAlex.
- Impact of Genetic Variants Associated with Neurodevelopmental Disorders on the WAVE Regulatory Complex.Journal of chemical information and modeling · 2025Article
- Talin, a Rap1 effector for integrin activation at the plasma membrane, also promotes Rap1 activity by disrupting sequestration of Rap1 by SHANK3.Journal of cell science · 2025Article
- Simulated complexes formed from a set of postsynaptic proteins suggest a localised effect of a hypomorphic Shank mutation.BMC neuroscience · 2024Article
- Evidence for common mechanisms of pathology between SHANK3 and other genes of Phelan-McDermid syndrome.Clinical genetics · 2024Review
- The Shank/ProSAP N-Terminal (SPN) Domain of Shank3 Regulates Targeting to Postsynaptic Sites and Postsynaptic Signaling.Molecular neurobiology · 2024Article
- Elevated SH3 and Multiple Ankyrin Repeat Domains 2 Expression Correlates With Improved Glioma Prognosis.International journal of genomics · 2024Article
- SHANK family on stem cell fate and development.Cell death & disease · 2022Review
- Association of SHANK Family with Neuropsychiatric Disorders: An Update on Genetic and Animal Model Discoveries.Cellular and molecular neurobiology · 2022Review
- A recurrent SHANK1 mutation implicated in autism spectrum disorder causes autistic-like core behaviors in mice via downregulation of mGluR1-IP3R1-calcium signaling.Molecular psychiatry · 2022Article
- SHARPIN: Role in Finding NEMO and in Amyloid-Beta Clearance and Degradation (ABCD) Pathway in Alzheimer's Disease?Cellular and molecular neurobiology · 2022Review
- Mutations affecting the N-terminal domains of SHANK3 point to different pathomechanisms in neurodevelopmental disorders.Scientific reports · 2022Article
- Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications.Journal of neurodevelopmental disorders · 2021Review
- Symptomatic, Genetic, and Mechanistic Overlaps between Autism and Alzheimer's Disease.Biomolecules · 2021Review
- Genetic Findings as the Potential Basis of Personalized Pharmacotherapy in Phelan-McDermid Syndrome.Genes · 2021Review
- Autism-associatedeLife · 2021Article
- Case Report: Lennox-Gastaut Epileptic Encephalopathy Responsive to Cannabidiol Treatment Associated With a NovelFrontiers in genetics · 2021Article
- Shankopathies in the Developing Brain in Autism Spectrum Disorders.Frontiers in neuroscience · 2021Review
- Targeting of δ-catenin to postsynaptic sites through interaction with the Shank3 N-terminus.Molecular autism · 2020Article
- Article
- Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations.Scientific reports · 2019Article
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Authors and funding
12 authors at 8 institutions in 3 countries.
Funding
Abstract
Shank/ProSAP proteins are major scaffold proteins of the postsynaptic density; mutations in the human SHANK3 gene are associated with intellectual disability or autism spectrum disorders. We have analyzed the functional relevance of several SHANK3 missense mutations affecting the N-terminal portion of the protein by expression of wild-type and mutant Shank3 in cultured neurons and by binding assays in heterologous cells. Postsynaptic targeting of recombinant Shank3 was unaltered. In electrophysiological experiments, both wild-type and L68P mutant forms of Shank3 were equally effective in restoring synaptic function after knockdown of endogenous Shank3. We observed that several mutations affected binding to interaction partners of the Shank3 ankyrin repeat region. One of these mutations, L68P, improved binding to both ligands. Leu-68 is located N-terminal to the ankyrin repeats, in a highly conserved region that we identify here as a novel domain termed the Shank/ProSAP N-terminal (SPN) domain. We show that the SPN domain interacts with the ankyrin repeats in an intramolecular manner, thereby restricting access of either Sharpin or α-fodrin. The L68P mutation disrupts this blockade, thus exposing the Shank3 ankyrin repeat region to its ligands. Our data identify a new type of regulation of Shank proteins and suggest that mutations in the SHANK3 gene do not necessarily induce a loss of function, but may represent a gain of function with respect to specific interaction partners.
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