The SPN domain has been shown to interact with small GTPases of the Ras superfamily including R-Ras, H-Ras or Rap1, which are involved in the regulation of synaptic F-actin structure and dynamics and in postsynaptic signal transduction ( Cai et al., 2020 Lilja et al., 2017). These include the SHANK/ProSAP N-terminal (SPN) domain followed by the ankyrin repeat region (ARR), a Src homology 3 (SH3) domain, the PSD-95/DLG/ZO-1 (PDZ) domain, and the C-terminal sterile alpha motif (SAM). The SHANK3a isoform shows highest expression in the striatum and hippocampus and consists of five distinct domains plus an additional proline-rich cluster ( Jiang and Ehlers, 2013 Wang et al., 2014b). To date, multiple splice isoforms of SHANK3 with varying domain organization have been identified ( Wang et al., 2014a). SHANK3 is a multidomain synaptic scaffold protein most prominently expressed in the brain ( Grabrucker et al., 2011). Establishing such structure-function relationships will contribute to a better understanding of pathogenic mechanisms in particular for autism spectrum disorder (ASD Luo et al., 2018 Stefl et al., 2013). Currently, very little is known about how such missense mutations alter protein structure and conformational stability in a manner that might cause disease-related synaptic phenotypes. Center for Behavioral Brain Sciences, Germany ĭe novo and inherited point mutations contribute to several neuropsychiatric disorders and are common in genes that are responsible for synaptic function ( Gratten et al., 2013 Hammer et al., 2015 Penzes et al., 2011).German Center for Neurodegenerative Diseases, Germany.Leibniz Group 'Dendritic Organelles and Synaptic Function', Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Germany.The Gene and Linda Voiland School of Chemical Engineering and Bioengineering, Washington State University (WSU), United States.Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS) and Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Republic of Korea.Institute of Human Genetics, Center for Obstetrics and Pediatrics, University Medical Center Hamburg-Eppendorf (UKE), Germany.European Molecular Biology Laboratory (EMBL) Hamburg Unit, DESY, Germany.Structural Cell Biology of Viruses, Centre for Structural Systems Biology (CSSB) and Leibniz Institute for Experimental Virology, Germany.Molecular Biophysics and High-Throughput Crystallization, European Molecular Biology Laboratory (EMBL), Germany.RG Neuroplasticity, Leibniz-Institute for Neurobiology (LIN), Germany.DFG Emmy Noether Guest Group 'Neuronal Protein Transport', Institute for Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Germany.AG Optobiology, Institute of Biology, Humboldt-University, Germany.
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