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

被引：19

作者：

Bucher, Michael ^{[1
,2
,3
]}

Niebling, Stephan ^{[4
]}

Han, Yuhao ^{[2
,5
,6
]}

Molodenskiy, Dmitry ^{[7
]}

Nia, Fatemeh Hassani ^{[8
]}

Kreienkamp, Hans-Juergen ^{[8
]}

Svergun, Dmitri ^{[7
]}

Kim, Eunjoon ^{[9
,10
]}

Kostyukova, Alla S. ^{[2
,11
]}

Kreutz, Michael R. ^{[3
,12
,13
,14
]}

Mikhaylova, Marina ^{[1
,2
]}

机构：

[1] Humboldt Univ, Inst Biol, AG Optobiol, Berlin, Germany

[2] Univ Med Ctr Hamburg Eppendorf UKE, Ctr Mol Neurobiol ZMNH, Inst Mol Neurogenet, DFG Emmy Noether Guest Grp Neuronal Prot Transpor, Hamburg, Germany

[3] Leibniz Inst Neurobiol LIN, RG Neuroplast, Magdeburg, Germany

[4] European Mol Biol Lab EMBL, Mol Biophys & High Throughput Crystallizat, Hamburg, Germany

[5] Ctr Struct Syst Biol CSSB, Struct Cell Biol Viruses, Hamburg, Germany

[6] Leibniz Inst Expt Virol, Hamburg, Germany

[7] DESY, European Mol Biol Lab EMBL, Hamburg Unit, Hamburg, Germany

[8] Univ Med Ctr Hamburg Eppendorf UKE, Ctr Obstet & Pediat, Inst Human Genet, Hamburg, Germany

[9] Korea Adv Inst Sci & Technol KAIST, Ctr Synapt Brain Dysfunct, Inst Basic Sci IBS, Daejeon, South Korea

[10] Korea Adv Inst Sci & Technol KAIST, Dept Biol Sci, Daejeon, South Korea

[11] Washington State Univ WSU, Gene & Linda Voiland Sch Chem Engn & Bioengn, Pullman, WA USA

[12] Univ Med Ctr Hamburg Eppendorf UKE, Ctr Mol Neurobiol ZMNH, Leibniz Grp Dendrit Organelles & Synapt Funct, Hamburg, Germany

[13] German Ctr Neurodegenerat Dis, Magdeburg, Germany

[14] Ctr Behav Brain Sci, Magdeburg, Germany

来源：

ELIFE | 2021年 / 10卷

关键词：

POSTSYNAPTIC DENSITY PROTEINS; SMALL-ANGLE SCATTERING; PARTICLE MESH EWALD; X-RAY-SCATTERING; MOLECULAR-DYNAMICS; GENE-MUTATIONS; FAMILY; VISUALIZATION; COMPLEX; BINDING;

D O I：

10.7554/eLife.66165

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页数：31

共 86 条

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