Functional diversity and structural disorder in the human ubiquitination pathway.

The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By col...

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Autores principales:	Pallab Bhowmick, Rita Pancsa, Mainak Guharoy, Peter Tompa
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bc5e98eb2c4f4b26bf02a7a8619e70d1
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spelling	oai:doaj.org-article:bc5e98eb2c4f4b26bf02a7a8619e70d12021-11-18T07:43:51ZFunctional diversity and structural disorder in the human ubiquitination pathway.1932-620310.1371/journal.pone.0065443https://doaj.org/article/bc5e98eb2c4f4b26bf02a7a8619e70d12013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23734257/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions.Pallab BhowmickRita PancsaMainak GuharoyPeter TompaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e65443 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pallab Bhowmick Rita Pancsa Mainak Guharoy Peter Tompa Functional diversity and structural disorder in the human ubiquitination pathway.
description	The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions.
format	article
author	Pallab Bhowmick Rita Pancsa Mainak Guharoy Peter Tompa
author_facet	Pallab Bhowmick Rita Pancsa Mainak Guharoy Peter Tompa
author_sort	Pallab Bhowmick
title	Functional diversity and structural disorder in the human ubiquitination pathway.
title_short	Functional diversity and structural disorder in the human ubiquitination pathway.
title_full	Functional diversity and structural disorder in the human ubiquitination pathway.
title_fullStr	Functional diversity and structural disorder in the human ubiquitination pathway.
title_full_unstemmed	Functional diversity and structural disorder in the human ubiquitination pathway.
title_sort	functional diversity and structural disorder in the human ubiquitination pathway.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/bc5e98eb2c4f4b26bf02a7a8619e70d1
work_keys_str_mv	AT pallabbhowmick functionaldiversityandstructuraldisorderinthehumanubiquitinationpathway AT ritapancsa functionaldiversityandstructuraldisorderinthehumanubiquitinationpathway AT mainakguharoy functionaldiversityandstructuraldisorderinthehumanubiquitinationpathway AT petertompa functionaldiversityandstructuraldisorderinthehumanubiquitinationpathway
_version_	1718423059405209600

Functional diversity and structural disorder in the human ubiquitination pathway.

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