Autism-associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses

eLife

Marina Mikhaylova¹  Michael Bucher²  Eunjoon Kim³  Yuhao Han⁴  Alla S Kostyukova⁵  Dmitry Molodenskiy⁶  Dmitri Svergun⁶  Hans-Jürgen Kreienkamp⁷  Fatemeh Hassani Nia⁷  Stephan Niebling⁸  Michael R Kreutz⁹ 

[1] AG Optobiology, Institute of Biology, Humboldt-University, Berlin, Germany;DFG Emmy Noether Guest Group 'Neuronal Protein Transport', Institute for Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany;AG Optobiology, Institute of Biology, Humboldt-University, Berlin, Germany;DFG Emmy Noether Guest Group 'Neuronal Protein Transport', Institute for Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany;RG Neuroplasticity, Leibniz-Institute for Neurobiology (LIN), Magdeburg, Germany;Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS) and Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea;DFG Emmy Noether Guest Group 'Neuronal Protein Transport', Institute for Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany;Structural Cell Biology of Viruses, Centre for Structural Systems Biology (CSSB) and Leibniz Institute for Experimental Virology, Hamburg, Germany;DFG Emmy Noether Guest Group 'Neuronal Protein Transport', Institute for Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany;The Gene and Linda Voiland School of Chemical Engineering and Bioengineering, Washington State University (WSU), Pullman, United States;European Molecular Biology Laboratory (EMBL) Hamburg Unit, DESY, Hamburg, Germany;Institute of Human Genetics, Center for Obstetrics and Pediatrics, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany;Molecular Biophysics and High-Throughput Crystallization, European Molecular Biology Laboratory (EMBL), Hamburg, Germany;RG Neuroplasticity, Leibniz-Institute for Neurobiology (LIN), Magdeburg, Germany;Leibniz Group 'Dendritic Organelles and Synaptic Function', Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany;German Center for Neurodegenerative Diseases, Magdeburg, Germany;Center for Behavioral Brain Sciences, Magdeburg, Germany;

关键词: conformational dynamics;    SHANK3;    protein folding;    postsynaptic density;    synaptic protein turnover;    autism;    Rat;   

DOI  :  10.7554/eLife.66165

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Members of the SH3- and ankyrin repeat (SHANK) protein family are considered as master scaffolds of the postsynaptic density of glutamatergic synapses. Several missense mutations within the canonical SHANK3 isoform have been proposed as causative for the development of autism spectrum disorders (ASDs). However, there is a surprising paucity of data linking missense mutation-induced changes in protein structure and dynamics to the occurrence of ASD-related synaptic phenotypes. In this proof-of-principle study, we focus on two ASD-associated point mutations, both located within the same domain of SHANK3 and demonstrate that both mutant proteins indeed show distinct changes in secondary and tertiary structure as well as higher conformational fluctuations. Local and distal structural disturbances result in altered synaptic targeting and changes of protein turnover at synaptic sites in rat primary hippocampal neurons.

【 授权许可】

CC BY