Genome-wide analysis of PDZ domain binding reveals inherent functional overlap within the PDZ interaction network.

Binding selectivity and cross-reactivity within one of the largest and most abundant interaction domain families, the PDZ family, has long been enigmatic. The complete human PDZ domain complement (the PDZome) consists of 267 domains and we applied here a Bayesian selectivity model to predict hundred...

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Autores principales:	Aartjan J W te Velthuis, Philippe A Sakalis, Donald A Fowler, Christoph P Bagowski
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/94cb0839d44940aa8dfeeb6c97fca5d0
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spelling	oai:doaj.org-article:94cb0839d44940aa8dfeeb6c97fca5d02021-11-18T07:00:00ZGenome-wide analysis of PDZ domain binding reveals inherent functional overlap within the PDZ interaction network.1932-620310.1371/journal.pone.0016047https://doaj.org/article/94cb0839d44940aa8dfeeb6c97fca5d02011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21283644/?tool=EBIhttps://doaj.org/toc/1932-6203Binding selectivity and cross-reactivity within one of the largest and most abundant interaction domain families, the PDZ family, has long been enigmatic. The complete human PDZ domain complement (the PDZome) consists of 267 domains and we applied here a Bayesian selectivity model to predict hundreds of human PDZ domain interactions, using target sequences of 22,997 non-redundant proteins. Subsequent analysis of these binding scores shows that PDZs can be divided into two genome-wide clusters that coincide well with the division between canonical class 1 and 2 PDZs. Within the class 1 PDZs we observed binding overlap at unprecedented levels, mediated by two residues at positions 1 and 5 of the second α-helix of the binding pocket. Eight PDZ domains were subsequently selected for experimental binding studies and to verify the basics of our predictions. Overall, the PDZ domain class 1 cross-reactivity identified here implies that auxiliary mechanisms must be in place to overcome this inherent functional overlap and to minimize cross-selectivity within the living cell. Indeed, when we superimpose PDZ domain binding affinities with gene ontologies, network topology data and the domain position within a PDZ superfamily protein, functional overlap is minimized and PDZ domains position optimally in the binding space. We therefore propose that PDZ domain selectivity is achieved through cellular context rather than inherent binding specificity.Aartjan J W te VelthuisPhilippe A SakalisDonald A FowlerChristoph P BagowskiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 1, p e16047 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Aartjan J W te Velthuis Philippe A Sakalis Donald A Fowler Christoph P Bagowski Genome-wide analysis of PDZ domain binding reveals inherent functional overlap within the PDZ interaction network.
description	Binding selectivity and cross-reactivity within one of the largest and most abundant interaction domain families, the PDZ family, has long been enigmatic. The complete human PDZ domain complement (the PDZome) consists of 267 domains and we applied here a Bayesian selectivity model to predict hundreds of human PDZ domain interactions, using target sequences of 22,997 non-redundant proteins. Subsequent analysis of these binding scores shows that PDZs can be divided into two genome-wide clusters that coincide well with the division between canonical class 1 and 2 PDZs. Within the class 1 PDZs we observed binding overlap at unprecedented levels, mediated by two residues at positions 1 and 5 of the second α-helix of the binding pocket. Eight PDZ domains were subsequently selected for experimental binding studies and to verify the basics of our predictions. Overall, the PDZ domain class 1 cross-reactivity identified here implies that auxiliary mechanisms must be in place to overcome this inherent functional overlap and to minimize cross-selectivity within the living cell. Indeed, when we superimpose PDZ domain binding affinities with gene ontologies, network topology data and the domain position within a PDZ superfamily protein, functional overlap is minimized and PDZ domains position optimally in the binding space. We therefore propose that PDZ domain selectivity is achieved through cellular context rather than inherent binding specificity.
format	article
author	Aartjan J W te Velthuis Philippe A Sakalis Donald A Fowler Christoph P Bagowski
author_facet	Aartjan J W te Velthuis Philippe A Sakalis Donald A Fowler Christoph P Bagowski
author_sort	Aartjan J W te Velthuis
title	Genome-wide analysis of PDZ domain binding reveals inherent functional overlap within the PDZ interaction network.
title_short	Genome-wide analysis of PDZ domain binding reveals inherent functional overlap within the PDZ interaction network.
title_full	Genome-wide analysis of PDZ domain binding reveals inherent functional overlap within the PDZ interaction network.
title_fullStr	Genome-wide analysis of PDZ domain binding reveals inherent functional overlap within the PDZ interaction network.
title_full_unstemmed	Genome-wide analysis of PDZ domain binding reveals inherent functional overlap within the PDZ interaction network.
title_sort	genome-wide analysis of pdz domain binding reveals inherent functional overlap within the pdz interaction network.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/94cb0839d44940aa8dfeeb6c97fca5d0
work_keys_str_mv	AT aartjanjwtevelthuis genomewideanalysisofpdzdomainbindingrevealsinherentfunctionaloverlapwithinthepdzinteractionnetwork AT philippeasakalis genomewideanalysisofpdzdomainbindingrevealsinherentfunctionaloverlapwithinthepdzinteractionnetwork AT donaldafowler genomewideanalysisofpdzdomainbindingrevealsinherentfunctionaloverlapwithinthepdzinteractionnetwork AT christophpbagowski genomewideanalysisofpdzdomainbindingrevealsinherentfunctionaloverlapwithinthepdzinteractionnetwork
_version_	1718424118622158848

Genome-wide analysis of PDZ domain binding reveals inherent functional overlap within the PDZ interaction network.

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