Structural basis for specific interaction of TGFβ signalling regulators SARA/endofin with HD-PTP

Deepanker Gahloth; Colin Levy; Louise Walker; Lydia Wunderley; AP Mould; Sandra Taylor; Philip Woodman; Lydia Tabernero

doi:10.1016/j.str.2017.05.005

Structural basis for specific interaction of TGFβ signalling regulators SARA/endofin with HD-PTP

Deepanker Gahloth, Colin Levy, Louise Walker, Lydia Wunderley, AP Mould, Sandra Taylor, Philip Woodman, Lydia Tabernero

Research output: Contribution to journal › Article › peer-review

Abstract

SARA and endofin are endosomal adaptor proteins that drive Smad phosphorylation by ligand-activated TGFβ/BMP receptors. We show in this study that SARA and endofin also recruit the tumour supressor HD-PTP, a master regulator of endosomal sorting and ESCRT-dependent receptor down-regulation. High affinity interactions occur between the SARA/endofin N-termini, and the conserved hydrophobic region in the HD-PTP Bro1 domain that binds CHMP4/ESCRT-III. CHMP4 engagement is a universal feature of Bro1 proteins, but SARA/endofin binding is specific to HD-PTP. Crystallographic structures of HD-PTP_Bro1 in complex with SARA, endofin and three CHMP4 isoforms
revealed that all ligands bind similarly to the conserved site, but critically, only
SARA/endofin interact at a neighbouring pocket unique to HD-PTP. The structures, together with mutagenesis and binding analysis, explain the high affinity and specific binding of SARA/endofin, and why they compete so effectively with CHMP4. Our data invoke models for how endocytic regulation of TGFβ/BMP signalling is controlled.

Original language	English
Journal	Structure
Early online date	8 Jun 2017
DOIs	https://doi.org/10.1016/j.str.2017.05.005
Publication status	Published - 2017

Keywords

TGFβ signalling
tumour supressor phosphatase
ESCRT-III
SARA and endofin
crystallographic structures
endosomal effectors

Research Beacons, Institutes and Platforms

Manchester Institute of Biotechnology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.str.2017.05.005Licence: CC BY

Biological Mass Spectrometry (BioMS) Facility
Knight, D. (Platform Lead), Warwood, S. (Senior Technical Specialist), Selley, J. (Technical Specialist), Taylor, G. (Technical Specialist), Fullwood, P. (Technical Specialist), Keevill, E.-J. (Senior Technician) & Allsey, J. (Technician)
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@article{05f577d014244948989486fd7c93ebfb,

title = "Structural basis for specific interaction of TGFβ signalling regulators SARA/endofin with HD-PTP",

abstract = "SARA and endofin are endosomal adaptor proteins that drive Smad phosphorylation by ligand-activated TGFβ/BMP receptors. We show in this study that SARA and endofin also recruit the tumour supressor HD-PTP, a master regulator of endosomal sorting and ESCRT-dependent receptor down-regulation. High affinity interactions occur between the SARA/endofin N-termini, and the conserved hydrophobic region in the HD-PTP Bro1 domain that binds CHMP4/ESCRT-III. CHMP4 engagement is a universal feature of Bro1 proteins, but SARA/endofin binding is specific to HD-PTP. Crystallographic structures of HD-PTPBro1 in complex with SARA, endofin and three CHMP4 isoformsrevealed that all ligands bind similarly to the conserved site, but critically, onlySARA/endofin interact at a neighbouring pocket unique to HD-PTP. The structures, together with mutagenesis and binding analysis, explain the high affinity and specific binding of SARA/endofin, and why they compete so effectively with CHMP4. Our data invoke models for how endocytic regulation of TGFβ/BMP signalling is controlled.",

keywords = "TGFβ signalling, tumour supressor phosphatase, ESCRT-III, SARA and endofin, crystallographic structures, endosomal effectors",

author = "Deepanker Gahloth and Colin Levy and Louise Walker and Lydia Wunderley and AP Mould and Sandra Taylor and Philip Woodman and Lydia Tabernero",

year = "2017",

doi = "10.1016/j.str.2017.05.005",

language = "English",

journal = "Structure",

issn = "1878-4186",

publisher = "Cell Press",

}

TY - JOUR

T1 - Structural basis for specific interaction of TGFβ signalling regulators SARA/endofin with HD-PTP

AU - Gahloth, Deepanker

AU - Levy, Colin

AU - Walker, Louise

AU - Wunderley, Lydia

AU - Mould, AP

AU - Taylor, Sandra

AU - Woodman, Philip

AU - Tabernero, Lydia

PY - 2017

Y1 - 2017

N2 - SARA and endofin are endosomal adaptor proteins that drive Smad phosphorylation by ligand-activated TGFβ/BMP receptors. We show in this study that SARA and endofin also recruit the tumour supressor HD-PTP, a master regulator of endosomal sorting and ESCRT-dependent receptor down-regulation. High affinity interactions occur between the SARA/endofin N-termini, and the conserved hydrophobic region in the HD-PTP Bro1 domain that binds CHMP4/ESCRT-III. CHMP4 engagement is a universal feature of Bro1 proteins, but SARA/endofin binding is specific to HD-PTP. Crystallographic structures of HD-PTPBro1 in complex with SARA, endofin and three CHMP4 isoformsrevealed that all ligands bind similarly to the conserved site, but critically, onlySARA/endofin interact at a neighbouring pocket unique to HD-PTP. The structures, together with mutagenesis and binding analysis, explain the high affinity and specific binding of SARA/endofin, and why they compete so effectively with CHMP4. Our data invoke models for how endocytic regulation of TGFβ/BMP signalling is controlled.

AB - SARA and endofin are endosomal adaptor proteins that drive Smad phosphorylation by ligand-activated TGFβ/BMP receptors. We show in this study that SARA and endofin also recruit the tumour supressor HD-PTP, a master regulator of endosomal sorting and ESCRT-dependent receptor down-regulation. High affinity interactions occur between the SARA/endofin N-termini, and the conserved hydrophobic region in the HD-PTP Bro1 domain that binds CHMP4/ESCRT-III. CHMP4 engagement is a universal feature of Bro1 proteins, but SARA/endofin binding is specific to HD-PTP. Crystallographic structures of HD-PTPBro1 in complex with SARA, endofin and three CHMP4 isoformsrevealed that all ligands bind similarly to the conserved site, but critically, onlySARA/endofin interact at a neighbouring pocket unique to HD-PTP. The structures, together with mutagenesis and binding analysis, explain the high affinity and specific binding of SARA/endofin, and why they compete so effectively with CHMP4. Our data invoke models for how endocytic regulation of TGFβ/BMP signalling is controlled.

KW - TGFβ signalling

KW - tumour supressor phosphatase

KW - ESCRT-III

KW - SARA and endofin

KW - crystallographic structures

KW - endosomal effectors

U2 - 10.1016/j.str.2017.05.005

DO - 10.1016/j.str.2017.05.005

M3 - Article

SN - 1878-4186

JO - Structure

JF - Structure

ER -

Structural basis for specific interaction of TGFβ signalling regulators SARA/endofin with HD-PTP

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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Equipment

Biological Mass Spectrometry (BioMS) Facility

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