Post-translational modifications modulate ligand recognition by the third PDZ domain of the MAGUK protein PSD-95.

The relative promiscuity of hub proteins such as postsynaptic density protein-95 (PSD-95) can be achieved by alternative splicing, allosteric regulation, and post-translational modifications, the latter of which is the most efficient method of accelerating cellular responses to environmental changes...

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Autores principales:	Javier Murciano-Calles, Carles Corbi-Verge, Adela M Candel, Irene Luque, Jose C Martinez
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6e1b528ce45546eb8b51715f834eb22b
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spelling	oai:doaj.org-article:6e1b528ce45546eb8b51715f834eb22b2021-11-18T08:30:48ZPost-translational modifications modulate ligand recognition by the third PDZ domain of the MAGUK protein PSD-95.1932-620310.1371/journal.pone.0090030https://doaj.org/article/6e1b528ce45546eb8b51715f834eb22b2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24587199/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The relative promiscuity of hub proteins such as postsynaptic density protein-95 (PSD-95) can be achieved by alternative splicing, allosteric regulation, and post-translational modifications, the latter of which is the most efficient method of accelerating cellular responses to environmental changes in vivo. Here, a mutational approach was used to determine the impact of phosphorylation and succinimidation post-translational modifications on the binding affinity of the postsynaptic density protein-95/discs large/zonula occludens-1 (PDZ3) domain of PSD-95. Molecular dynamics simulations revealed that the binding affinity of this domain is influenced by an interplay between salt-bridges linking the α3 helix, the β2-β3 loop and the positively charged Lys residues in its high-affinity hexapeptide ligand KKETAV. The α3 helix is an extra structural element that is not present in other PDZ domains, which links PDZ3 with the following SH3 domain in the PSD-95 protein. This regulatory mechanism was confirmed experimentally via thermodynamic and NMR chemical shift perturbation analyses, discarding intra-domain long-range effects. Taken together, the results presented here reveal the molecular basis of the regulatory role of the α3 extra-element and the effects of post-translational modifications of PDZ3 on its binding affinity, both energetically and dynamically.Javier Murciano-CallesCarles Corbi-VergeAdela M CandelIrene LuqueJose C MartinezPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 2, p e90030 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Javier Murciano-Calles Carles Corbi-Verge Adela M Candel Irene Luque Jose C Martinez Post-translational modifications modulate ligand recognition by the third PDZ domain of the MAGUK protein PSD-95.
description	The relative promiscuity of hub proteins such as postsynaptic density protein-95 (PSD-95) can be achieved by alternative splicing, allosteric regulation, and post-translational modifications, the latter of which is the most efficient method of accelerating cellular responses to environmental changes in vivo. Here, a mutational approach was used to determine the impact of phosphorylation and succinimidation post-translational modifications on the binding affinity of the postsynaptic density protein-95/discs large/zonula occludens-1 (PDZ3) domain of PSD-95. Molecular dynamics simulations revealed that the binding affinity of this domain is influenced by an interplay between salt-bridges linking the α3 helix, the β2-β3 loop and the positively charged Lys residues in its high-affinity hexapeptide ligand KKETAV. The α3 helix is an extra structural element that is not present in other PDZ domains, which links PDZ3 with the following SH3 domain in the PSD-95 protein. This regulatory mechanism was confirmed experimentally via thermodynamic and NMR chemical shift perturbation analyses, discarding intra-domain long-range effects. Taken together, the results presented here reveal the molecular basis of the regulatory role of the α3 extra-element and the effects of post-translational modifications of PDZ3 on its binding affinity, both energetically and dynamically.
format	article
author	Javier Murciano-Calles Carles Corbi-Verge Adela M Candel Irene Luque Jose C Martinez
author_facet	Javier Murciano-Calles Carles Corbi-Verge Adela M Candel Irene Luque Jose C Martinez
author_sort	Javier Murciano-Calles
title	Post-translational modifications modulate ligand recognition by the third PDZ domain of the MAGUK protein PSD-95.
title_short	Post-translational modifications modulate ligand recognition by the third PDZ domain of the MAGUK protein PSD-95.
title_full	Post-translational modifications modulate ligand recognition by the third PDZ domain of the MAGUK protein PSD-95.
title_fullStr	Post-translational modifications modulate ligand recognition by the third PDZ domain of the MAGUK protein PSD-95.
title_full_unstemmed	Post-translational modifications modulate ligand recognition by the third PDZ domain of the MAGUK protein PSD-95.
title_sort	post-translational modifications modulate ligand recognition by the third pdz domain of the maguk protein psd-95.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/6e1b528ce45546eb8b51715f834eb22b
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Post-translational modifications modulate ligand recognition by the third PDZ domain of the MAGUK protein PSD-95.

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