Site-specific phosphorylation of PSD-95 dynamically regulates the postsynaptic density as observed by phase separation

Summary: Postsynaptic density protein 95 is a key scaffolding protein in the postsynaptic density of excitatory glutamatergic neurons, organizing signaling complexes primarily via its three PSD-95/Discs-large/Zona occludens domains. PSD-95 is regulated by phosphorylation, but technical challenges ha...

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Autores principales:	Maria Vistrup-Parry, Xudong Chen, Thea L. Johansen, Sofie Bach, Sara C. Buch-Larsen, Christian R.O. Bartling, Chenxue Ma, Louise S. Clemmensen, Michael L. Nielsen, Mingjie Zhang, Kristian Strømgaard
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Biochemistry Biomolecules Protein structure aspects Biophysics Biophysical chemistry Science Q
Acceso en línea:	https://doaj.org/article/c0fa66c067824ad998d2b160f87425b6
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spelling	oai:doaj.org-article:c0fa66c067824ad998d2b160f87425b62021-11-20T05:09:06ZSite-specific phosphorylation of PSD-95 dynamically regulates the postsynaptic density as observed by phase separation2589-004210.1016/j.isci.2021.103268https://doaj.org/article/c0fa66c067824ad998d2b160f87425b62021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221012372https://doaj.org/toc/2589-0042Summary: Postsynaptic density protein 95 is a key scaffolding protein in the postsynaptic density of excitatory glutamatergic neurons, organizing signaling complexes primarily via its three PSD-95/Discs-large/Zona occludens domains. PSD-95 is regulated by phosphorylation, but technical challenges have limited studies of the molecular details. Here, we genetically introduced site-specific phosphorylations in single, tandem, and full-length PSD-95 and generated a total of 11 phosphorylated protein variants. We examined how these phosphorylations affected binding to known interaction partners and the impact on phase separation of PSD-95 complexes and identified two new phosphorylation sites with opposing effects. Phosphorylation of Ser78 inhibited phase separation with the glutamate receptor subunit GluN2B and the auxiliary protein stargazin, whereas phosphorylation of Ser116 induced phase separation with stargazin only. Thus, by genetically introducing phosphoserine site-specifically and exploring the impact on phase separation, we have provided new insights into the regulation of PSD-95 by phosphorylation and the dynamics of the PSD.Maria Vistrup-ParryXudong ChenThea L. JohansenSofie BachSara C. Buch-LarsenChristian R.O. BartlingChenxue MaLouise S. ClemmensenMichael L. NielsenMingjie ZhangKristian StrømgaardElsevierarticleBiochemistryBiomoleculesProtein structure aspectsBiophysicsBiophysical chemistryScienceQENiScience, Vol 24, Iss 11, Pp 103268- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biochemistry Biomolecules Protein structure aspects Biophysics Biophysical chemistry Science Q
spellingShingle	Biochemistry Biomolecules Protein structure aspects Biophysics Biophysical chemistry Science Q Maria Vistrup-Parry Xudong Chen Thea L. Johansen Sofie Bach Sara C. Buch-Larsen Christian R.O. Bartling Chenxue Ma Louise S. Clemmensen Michael L. Nielsen Mingjie Zhang Kristian Strømgaard Site-specific phosphorylation of PSD-95 dynamically regulates the postsynaptic density as observed by phase separation
description	Summary: Postsynaptic density protein 95 is a key scaffolding protein in the postsynaptic density of excitatory glutamatergic neurons, organizing signaling complexes primarily via its three PSD-95/Discs-large/Zona occludens domains. PSD-95 is regulated by phosphorylation, but technical challenges have limited studies of the molecular details. Here, we genetically introduced site-specific phosphorylations in single, tandem, and full-length PSD-95 and generated a total of 11 phosphorylated protein variants. We examined how these phosphorylations affected binding to known interaction partners and the impact on phase separation of PSD-95 complexes and identified two new phosphorylation sites with opposing effects. Phosphorylation of Ser78 inhibited phase separation with the glutamate receptor subunit GluN2B and the auxiliary protein stargazin, whereas phosphorylation of Ser116 induced phase separation with stargazin only. Thus, by genetically introducing phosphoserine site-specifically and exploring the impact on phase separation, we have provided new insights into the regulation of PSD-95 by phosphorylation and the dynamics of the PSD.
format	article
author	Maria Vistrup-Parry Xudong Chen Thea L. Johansen Sofie Bach Sara C. Buch-Larsen Christian R.O. Bartling Chenxue Ma Louise S. Clemmensen Michael L. Nielsen Mingjie Zhang Kristian Strømgaard
author_facet	Maria Vistrup-Parry Xudong Chen Thea L. Johansen Sofie Bach Sara C. Buch-Larsen Christian R.O. Bartling Chenxue Ma Louise S. Clemmensen Michael L. Nielsen Mingjie Zhang Kristian Strømgaard
author_sort	Maria Vistrup-Parry
title	Site-specific phosphorylation of PSD-95 dynamically regulates the postsynaptic density as observed by phase separation
title_short	Site-specific phosphorylation of PSD-95 dynamically regulates the postsynaptic density as observed by phase separation
title_full	Site-specific phosphorylation of PSD-95 dynamically regulates the postsynaptic density as observed by phase separation
title_fullStr	Site-specific phosphorylation of PSD-95 dynamically regulates the postsynaptic density as observed by phase separation
title_full_unstemmed	Site-specific phosphorylation of PSD-95 dynamically regulates the postsynaptic density as observed by phase separation
title_sort	site-specific phosphorylation of psd-95 dynamically regulates the postsynaptic density as observed by phase separation
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/c0fa66c067824ad998d2b160f87425b6
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Site-specific phosphorylation of PSD-95 dynamically regulates the postsynaptic density as observed by phase separation

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