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The open architecture of HD-PTP phosphatase provides new insights into the mechanism of regulation of ESCRT function

HD-PTP is a tumour suppressor phosphatase that controls endocytosis, down-regulation of mitogenic receptors and cell migration. Central to its role is the specific recruitment of critical endosomal sorting complexes required for transport (ESCRTs). However, the molecular mechanisms that enable HD-PT...

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Autores principales: Gahloth, Deepankar, Heaven, Graham, Jowitt, Thomas A., Mould, A. Paul, Bella, Jordi, Baldock, Clair, Woodman, Philip, Tabernero, Lydia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567221/
https://www.ncbi.nlm.nih.gov/pubmed/28831121
http://dx.doi.org/10.1038/s41598-017-09467-9
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author Gahloth, Deepankar
Heaven, Graham
Jowitt, Thomas A.
Mould, A. Paul
Bella, Jordi
Baldock, Clair
Woodman, Philip
Tabernero, Lydia
author_facet Gahloth, Deepankar
Heaven, Graham
Jowitt, Thomas A.
Mould, A. Paul
Bella, Jordi
Baldock, Clair
Woodman, Philip
Tabernero, Lydia
author_sort Gahloth, Deepankar
collection PubMed
description HD-PTP is a tumour suppressor phosphatase that controls endocytosis, down-regulation of mitogenic receptors and cell migration. Central to its role is the specific recruitment of critical endosomal sorting complexes required for transport (ESCRTs). However, the molecular mechanisms that enable HD-PTP to regulate ESCRT function are unknown. We have characterised the molecular architecture of the entire ESCRT binding region of HD-PTP using small angle X-ray scattering and hydrodynamic analyses. We show that HD-PTP adopts an open and extended conformation, optimal for concomitant interactions with multiple ESCRTs, which contrasts with the compact conformation of the related ESCRT regulator Alix. We demonstrate that the HD-PTP open conformation is functionally competent for binding cellular protein partners. Our analyses rationalise the functional cooperation of HD-PTP with ESCRT-0, ESCRT-I and ESCRT-III and support a model for regulation of ESCRT function by displacement of ESCRT subunits, which is crucial in determining the fate of ubiquitinated cargo.
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spelling pubmed-55672212017-09-01 The open architecture of HD-PTP phosphatase provides new insights into the mechanism of regulation of ESCRT function Gahloth, Deepankar Heaven, Graham Jowitt, Thomas A. Mould, A. Paul Bella, Jordi Baldock, Clair Woodman, Philip Tabernero, Lydia Sci Rep Article HD-PTP is a tumour suppressor phosphatase that controls endocytosis, down-regulation of mitogenic receptors and cell migration. Central to its role is the specific recruitment of critical endosomal sorting complexes required for transport (ESCRTs). However, the molecular mechanisms that enable HD-PTP to regulate ESCRT function are unknown. We have characterised the molecular architecture of the entire ESCRT binding region of HD-PTP using small angle X-ray scattering and hydrodynamic analyses. We show that HD-PTP adopts an open and extended conformation, optimal for concomitant interactions with multiple ESCRTs, which contrasts with the compact conformation of the related ESCRT regulator Alix. We demonstrate that the HD-PTP open conformation is functionally competent for binding cellular protein partners. Our analyses rationalise the functional cooperation of HD-PTP with ESCRT-0, ESCRT-I and ESCRT-III and support a model for regulation of ESCRT function by displacement of ESCRT subunits, which is crucial in determining the fate of ubiquitinated cargo. Nature Publishing Group UK 2017-08-22 /pmc/articles/PMC5567221/ /pubmed/28831121 http://dx.doi.org/10.1038/s41598-017-09467-9 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Gahloth, Deepankar
Heaven, Graham
Jowitt, Thomas A.
Mould, A. Paul
Bella, Jordi
Baldock, Clair
Woodman, Philip
Tabernero, Lydia
The open architecture of HD-PTP phosphatase provides new insights into the mechanism of regulation of ESCRT function
title The open architecture of HD-PTP phosphatase provides new insights into the mechanism of regulation of ESCRT function
title_full The open architecture of HD-PTP phosphatase provides new insights into the mechanism of regulation of ESCRT function
title_fullStr The open architecture of HD-PTP phosphatase provides new insights into the mechanism of regulation of ESCRT function
title_full_unstemmed The open architecture of HD-PTP phosphatase provides new insights into the mechanism of regulation of ESCRT function
title_short The open architecture of HD-PTP phosphatase provides new insights into the mechanism of regulation of ESCRT function
title_sort open architecture of hd-ptp phosphatase provides new insights into the mechanism of regulation of escrt function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567221/
https://www.ncbi.nlm.nih.gov/pubmed/28831121
http://dx.doi.org/10.1038/s41598-017-09467-9
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