Mutational Analysis of a Conserved Glutamate Reveals Unique Mechanistic and Structural Features of the Phosphatase PRL-3

ACS Omega
Birgit HoegerMaja Köhn

Abstract

Phosphatase of regenerating liver (PRL)-3 (PTP4A3) has gained much attention in cancer research due to its involvement in tumor promoting and metastatic processes. It belongs to the protein tyrosine phosphatase (PTP) superfamily and is thought to follow the catalytic mechanism shared by this family, which aside from the conserved active-site amino acids includes a conserved glutamic acid residue that is usually required for the integrity of the active site in PTPs. We noted that in structures of PRL-3, PRL-1, and PTEN these residues do not clearly align and therefore we sought to investigate if the glutamic acid residue fulfills its usual function in these proteins. Although this residue was essential for PTEN's catalytic activity, it was nonessential for PRL-1 and PRL-3. Surprisingly, the mutation E50R increased PRL-3 activity against all tested in vitro substrates and also enhanced PRL-3-promoted cell adhesion and migration. We show that the introduction of Arg50 leads to an enhancement of substrate turnover for both PRL-3 and, to a lesser extent, PRL-1, and that the stronger gain in activity correlates with a higher structural flexibility of PRL-3, likely allowing for conformational adaptation during catalysis. Thus, in cont...Continue Reading

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Citations

May 18, 2018·The FEBS Journal·Serge HardyMichel L Tremblay
Oct 12, 2019·The Journal of Pharmacology and Experimental Therapeutics·John S LazoElizabeth R Sharlow

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Methods Mentioned

BETA
X-ray
NMR
protein folding
Circular dichroism
Assay
confocal microscopy
ion-exchange chromatography
Circular
PCR
electrophoresis

Software Mentioned

GraphPad Prism
Fiji
Zeiss ZEN

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