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...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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Public Library of Science
2011
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| _version_ | 1797068487092338688 |
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| author | Te Velthuis, A Sakalis, P Fowler, D Bagowski, C |
| author_facet | Te Velthuis, A Sakalis, P Fowler, D Bagowski, C |
| author_sort | Te Velthuis, A |
| collection | OXFORD |
| 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. |
| first_indexed | 2024-03-06T22:11:26Z |
| format | Journal article |
| id | oxford-uuid:51efdae2-a3b5-4ccc-a9b0-d3ff4cc588da |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:11:26Z |
| publishDate | 2011 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:51efdae2-a3b5-4ccc-a9b0-d3ff4cc588da2022-03-26T16:22:37ZGenome-wide analysis of PDZ domain binding reveals inherent functional overlap within the PDZ interaction networkJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:51efdae2-a3b5-4ccc-a9b0-d3ff4cc588daEnglishSymplectic Elements at OxfordPublic Library of Science2011Te Velthuis, ASakalis, PFowler, DBagowski, CBinding 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. |
| spellingShingle | Te Velthuis, A Sakalis, P Fowler, D Bagowski, C Genome-wide analysis of PDZ domain binding reveals inherent functional overlap within the PDZ interaction network |
| title | 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_short | 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 |
| work_keys_str_mv | AT tevelthuisa genomewideanalysisofpdzdomainbindingrevealsinherentfunctionaloverlapwithinthepdzinteractionnetwork AT sakalisp genomewideanalysisofpdzdomainbindingrevealsinherentfunctionaloverlapwithinthepdzinteractionnetwork AT fowlerd genomewideanalysisofpdzdomainbindingrevealsinherentfunctionaloverlapwithinthepdzinteractionnetwork AT bagowskic genomewideanalysisofpdzdomainbindingrevealsinherentfunctionaloverlapwithinthepdzinteractionnetwork |