TY - JOUR TI - Autism-associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses AU - Bucher, Michael AU - Niebling, Stephan AU - Han, Yuhao AU - Molodenskiy, Dmitry AU - Hassani Nia, Fatemeh AU - Kreienkamp, Hans-Jürgen AU - Svergun, Dmitri AU - Kim, Eunjoon AU - Kostyukova, Alla S AU - Kreutz, Michael R AU - Mikhaylova, Marina A2 - Slutsky, Inna A2 - Boudker, Olga VL - 10 PY - 2021 DA - 2021/05/04 SP - e66165 C1 - eLife 2021;10:e66165 DO - 10.7554/eLife.66165 UR - https://doi.org/10.7554/eLife.66165 AB - 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. KW - conformational dynamics KW - SHANK3 KW - protein folding KW - postsynaptic density KW - synaptic protein turnover KW - autism JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -