Journal Article

PUBDB-2021-03943

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Autism-associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses

Bucher, M. ; Niebling, S.CFEL*Extern*EMBL* ; Han, Y.CSSB* ; Molodenskiy, D.EMBL* ; Hassani Nia, F. ; Kreienkamp, H.-J. ; Svergun, D.EMBL* ; Kim, E. ; Kostyukova, A. S. ; Kreutz, M. R. (Corresponding author) ; Mikhaylova, M. (Corresponding author)

2021
eLife Sciences Publications Cambridge

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Please use a persistent id in citations: doi:10.7554/eLife.66165  doi:10.3204/PUBDB-2021-03943

Abstract: 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.

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Contributing Institute(s):

1. EMBL (EMBL)
2. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. DFG project 390688087 - EXC 2049: Comprehensive approaches to neurological and psychiatric disorders "NeuroCure" (390688087) (390688087)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2021

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