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Crystal structure of the human Tip41 orthologue, TIPRL, reveals a novel fold and a binding site for the PP2Ac C-terminus

TOR signaling pathway regulator-like (TIPRL) is a regulatory protein which inhibits the catalytic subunits of Type 2A phosphatases. Several cellular contexts have been proposed for TIPRL, such as regulation of mTOR signaling, inhibition of apoptosis and biogenesis and recycling of PP2A, however, the...

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Autores principales: Scorsato, Valéria, Lima, Tatiani B., Righetto, Germanna L., Zanchin, Nilson I. T., Brandão-Neto, José, Sandy, James, Pereira, Humberto D’Muniz, Ferrari, Állan J. R., Gozzo, Fabio C., Smetana, Juliana H. C., Aparicio, Ricardo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973239/
https://www.ncbi.nlm.nih.gov/pubmed/27489114
http://dx.doi.org/10.1038/srep30813
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author Scorsato, Valéria
Lima, Tatiani B.
Righetto, Germanna L.
Zanchin, Nilson I. T.
Brandão-Neto, José
Sandy, James
Pereira, Humberto D’Muniz
Ferrari, Állan J. R.
Gozzo, Fabio C.
Smetana, Juliana H. C.
Aparicio, Ricardo
author_facet Scorsato, Valéria
Lima, Tatiani B.
Righetto, Germanna L.
Zanchin, Nilson I. T.
Brandão-Neto, José
Sandy, James
Pereira, Humberto D’Muniz
Ferrari, Állan J. R.
Gozzo, Fabio C.
Smetana, Juliana H. C.
Aparicio, Ricardo
author_sort Scorsato, Valéria
collection PubMed
description TOR signaling pathway regulator-like (TIPRL) is a regulatory protein which inhibits the catalytic subunits of Type 2A phosphatases. Several cellular contexts have been proposed for TIPRL, such as regulation of mTOR signaling, inhibition of apoptosis and biogenesis and recycling of PP2A, however, the underlying molecular mechanism is still poorly understood. We have solved the crystal structure of human TIPRL at 2.15 Å resolution. The structure is a novel fold organized around a central core of antiparallel beta-sheet, showing an N-terminal α/β region at one of its surfaces and a conserved cleft at the opposite surface. Inside this cleft, we found a peptide derived from TEV-mediated cleavage of the affinity tag. We show by mutagenesis, pulldown and hydrogen/deuterium exchange mass spectrometry that this peptide is a mimic for the conserved C-terminal tail of PP2A, an important region of the phosphatase which regulates holoenzyme assembly, and TIPRL preferentially binds the unmodified version of the PP2A-tail mimetic peptide DYFL compared to its tyrosine-phosphorylated version. A docking model of the TIPRL-PP2Ac complex suggests that TIPRL blocks the phosphatase’s active site, providing a structural framework for the function of TIPRL in PP2A inhibition.
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spelling pubmed-49732392016-08-11 Crystal structure of the human Tip41 orthologue, TIPRL, reveals a novel fold and a binding site for the PP2Ac C-terminus Scorsato, Valéria Lima, Tatiani B. Righetto, Germanna L. Zanchin, Nilson I. T. Brandão-Neto, José Sandy, James Pereira, Humberto D’Muniz Ferrari, Állan J. R. Gozzo, Fabio C. Smetana, Juliana H. C. Aparicio, Ricardo Sci Rep Article TOR signaling pathway regulator-like (TIPRL) is a regulatory protein which inhibits the catalytic subunits of Type 2A phosphatases. Several cellular contexts have been proposed for TIPRL, such as regulation of mTOR signaling, inhibition of apoptosis and biogenesis and recycling of PP2A, however, the underlying molecular mechanism is still poorly understood. We have solved the crystal structure of human TIPRL at 2.15 Å resolution. The structure is a novel fold organized around a central core of antiparallel beta-sheet, showing an N-terminal α/β region at one of its surfaces and a conserved cleft at the opposite surface. Inside this cleft, we found a peptide derived from TEV-mediated cleavage of the affinity tag. We show by mutagenesis, pulldown and hydrogen/deuterium exchange mass spectrometry that this peptide is a mimic for the conserved C-terminal tail of PP2A, an important region of the phosphatase which regulates holoenzyme assembly, and TIPRL preferentially binds the unmodified version of the PP2A-tail mimetic peptide DYFL compared to its tyrosine-phosphorylated version. A docking model of the TIPRL-PP2Ac complex suggests that TIPRL blocks the phosphatase’s active site, providing a structural framework for the function of TIPRL in PP2A inhibition. Nature Publishing Group 2016-08-04 /pmc/articles/PMC4973239/ /pubmed/27489114 http://dx.doi.org/10.1038/srep30813 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Scorsato, Valéria
Lima, Tatiani B.
Righetto, Germanna L.
Zanchin, Nilson I. T.
Brandão-Neto, José
Sandy, James
Pereira, Humberto D’Muniz
Ferrari, Állan J. R.
Gozzo, Fabio C.
Smetana, Juliana H. C.
Aparicio, Ricardo
Crystal structure of the human Tip41 orthologue, TIPRL, reveals a novel fold and a binding site for the PP2Ac C-terminus
title Crystal structure of the human Tip41 orthologue, TIPRL, reveals a novel fold and a binding site for the PP2Ac C-terminus
title_full Crystal structure of the human Tip41 orthologue, TIPRL, reveals a novel fold and a binding site for the PP2Ac C-terminus
title_fullStr Crystal structure of the human Tip41 orthologue, TIPRL, reveals a novel fold and a binding site for the PP2Ac C-terminus
title_full_unstemmed Crystal structure of the human Tip41 orthologue, TIPRL, reveals a novel fold and a binding site for the PP2Ac C-terminus
title_short Crystal structure of the human Tip41 orthologue, TIPRL, reveals a novel fold and a binding site for the PP2Ac C-terminus
title_sort crystal structure of the human tip41 orthologue, tiprl, reveals a novel fold and a binding site for the pp2ac c-terminus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973239/
https://www.ncbi.nlm.nih.gov/pubmed/27489114
http://dx.doi.org/10.1038/srep30813
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