Beyond the binding site: the role of the β₂-β₃ loop and extra-domain structures in PDZ domains.

A general paradigm to understand protein function is to look at properties of isolated well conserved domains, such as SH3 or PDZ domains. While common features of domain families are well understood, the role of subtle differences among members of these families is less clear. Here, molecular dynam...

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Autores principales:	Stefano Mostarda, David Gfeller, Francesco Rao
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/bea6f33955b1473c9f9e7ce2d134174d
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spelling	oai:doaj.org-article:bea6f33955b1473c9f9e7ce2d134174d2021-11-18T05:51:30ZBeyond the binding site: the role of the β₂-β₃ loop and extra-domain structures in PDZ domains.1553-734X1553-735810.1371/journal.pcbi.1002429https://doaj.org/article/bea6f33955b1473c9f9e7ce2d134174d2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22412368/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358A general paradigm to understand protein function is to look at properties of isolated well conserved domains, such as SH3 or PDZ domains. While common features of domain families are well understood, the role of subtle differences among members of these families is less clear. Here, molecular dynamics simulations indicate that the binding mechanism in PSD95-PDZ3 is critically regulated via interactions outside the canonical binding site, involving both the poorly conserved β₂-β₃ loop and an extra-domain helix. Using the CRIPT peptide as a prototypical ligand, our simulations suggest that a network of salt-bridges between the ligand and this loop is necessary for binding. These contacts interconvert between each other on a time scale of a few tens of nanoseconds, making them elusive to X-ray crystallography. The loop is stabilized by an extra-domain helix. The latter influences the global dynamics of the domain, considerably increasing binding affinity. We found that two key contacts between the helix and the domain, one involving the β₂-β₃ loop, provide an atomistic interpretation of the increased affinity. Our analysis indicates that both extra-domain segments and loosely conserved regions play critical roles in PDZ binding affinity and specificity.Stefano MostardaDavid GfellerFrancesco RaoPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 8, Iss 3, p e1002429 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Stefano Mostarda David Gfeller Francesco Rao Beyond the binding site: the role of the β₂-β₃ loop and extra-domain structures in PDZ domains.
description	A general paradigm to understand protein function is to look at properties of isolated well conserved domains, such as SH3 or PDZ domains. While common features of domain families are well understood, the role of subtle differences among members of these families is less clear. Here, molecular dynamics simulations indicate that the binding mechanism in PSD95-PDZ3 is critically regulated via interactions outside the canonical binding site, involving both the poorly conserved β₂-β₃ loop and an extra-domain helix. Using the CRIPT peptide as a prototypical ligand, our simulations suggest that a network of salt-bridges between the ligand and this loop is necessary for binding. These contacts interconvert between each other on a time scale of a few tens of nanoseconds, making them elusive to X-ray crystallography. The loop is stabilized by an extra-domain helix. The latter influences the global dynamics of the domain, considerably increasing binding affinity. We found that two key contacts between the helix and the domain, one involving the β₂-β₃ loop, provide an atomistic interpretation of the increased affinity. Our analysis indicates that both extra-domain segments and loosely conserved regions play critical roles in PDZ binding affinity and specificity.
format	article
author	Stefano Mostarda David Gfeller Francesco Rao
author_facet	Stefano Mostarda David Gfeller Francesco Rao
author_sort	Stefano Mostarda
title	Beyond the binding site: the role of the β₂-β₃ loop and extra-domain structures in PDZ domains.
title_short	Beyond the binding site: the role of the β₂-β₃ loop and extra-domain structures in PDZ domains.
title_full	Beyond the binding site: the role of the β₂-β₃ loop and extra-domain structures in PDZ domains.
title_fullStr	Beyond the binding site: the role of the β₂-β₃ loop and extra-domain structures in PDZ domains.
title_full_unstemmed	Beyond the binding site: the role of the β₂-β₃ loop and extra-domain structures in PDZ domains.
title_sort	beyond the binding site: the role of the β₂-β₃ loop and extra-domain structures in pdz domains.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/bea6f33955b1473c9f9e7ce2d134174d
work_keys_str_mv	AT stefanomostarda beyondthebindingsitetheroleoftheb2b3loopandextradomainstructuresinpdzdomains AT davidgfeller beyondthebindingsitetheroleoftheb2b3loopandextradomainstructuresinpdzdomains AT francescorao beyondthebindingsitetheroleoftheb2b3loopandextradomainstructuresinpdzdomains
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Beyond the binding site: the role of the β₂-β₃ loop and extra-domain structures in PDZ domains.

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