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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Scorsato, Valeria ; Lima, Tatiani B. ; Righetto, Germanna L. ; Zanchin, Nilson I. T. ; Brandao-Neto, Jose ; Sandy, James ; Pereira, Humberto D'Muniz ; Ferrari, Allan J. R. ; Gozzo, Fabio C. ; Smetana, Juliana H. C. ; Aparicio, Ricardo
Total Authors: 11
Document type: Journal article
Source: SCIENTIFIC REPORTS; v. 6, AUG 4 2016.
Web of Science Citations: 5
Abstract

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 angstrom resolution. The structure is a novel fold organized around a central core of antiparallel beta-sheet, showing an N-terminal alpha/beta 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. (AU)

FAPESP's process: 11/03054-9 - Structural characterization of the human phosphatases PTP-1B and PP2A, involved in cancer, and their interactions with inhibitors
Grantee:Valeria Scorsato
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)