1. Autism-associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses
- Author
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Yuhao Han, Michael R. Kreutz, Marina Mikhaylova, Eunjoon Kim, Alla S. Kostyukova, Stephan Niebling, Fatemeh Hassani Nia, Dmitry S. Molodenskiy, Hans-Jürgen Kreienkamp, Michael Bucher, and Dmitri I. Svergun
- Subjects
Protein Conformation ,conformational dynamics ,physiology [Hippocampus] ,Hippocampus ,neuroscience ,protein folding ,SHANK3 ,synaptic protein turnover ,autism ,postsynaptic density ,rat ,Protein structure ,Missense mutation ,Biology (General) ,genetics [Nerve Tissue Proteins] ,Cells, Cultured ,Neurons ,General Neuroscience ,General Medicine ,physiology [Neurons] ,Cell biology ,genetics [Mutant Proteins] ,Medicine ,Research Article ,Protein family ,QH301-705.5 ,Science ,genetics [Mutation, Missense] ,Mutation, Missense ,Nerve Tissue Proteins ,Biology ,Molecular Dynamics Simulation ,Proof of Concept Study ,General Biochemistry, Genetics and Molecular Biology ,genetics [Autistic Disorder] ,Animals ,Point Mutation ,metabolism [Mutant Proteins] ,Autistic Disorder ,metabolism [Nerve Tissue Proteins] ,General Immunology and Microbiology ,Point mutation ,Protein turnover ,Protein tertiary structure ,Rats ,chemistry [Mutant Proteins] ,cytology [Hippocampus] ,Synapses ,Rat ,Ankyrin repeat ,Mutant Proteins ,physiology [Synapses] ,chemistry [Nerve Tissue Proteins] ,Postsynaptic density ,ddc:600 ,Neuroscience - Abstract
eLife 10, e66165 (1-31) (2021). doi:10.7554/eLife.66165, 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., Published by eLife Sciences Publications, Cambridge
- Published
- 2021
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