An unsuspected ecdysteroid/steroid phosphatase activity in the key T‐cell regulator, Sts‐1: Surprising relationship to insect ecdysteroid phosphate phosphatase

Davies, Lyndsay; Anderson, I. P.; Turner, Philip C.; Shirras, Alan D.; Rees, Huw H.; Rigden, Daniel J.

doi:10.1002/prot.21357

Cited by 25 publications

(30 citation statements)

References 60 publications

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“…Prednisolone 21-phosphate, a steroid phosphate that resembles E22P although with a shorter side chain, was shown to be substrate for EPPase (15). EPPase PGM (50 nM) hydrolyzes prednisolone 21-phosphate, dexamethasone 21-phosphate, and β-methasone 21-phosphate.…”

Section: Resultsmentioning

confidence: 99%

Structural and Functional Characterization of the C-Terminal Domain of the Ecdysteroid Phosphate Phosphatase from Bombyx mori Reveals a New Enzymatic Activity

et al. 2008

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Here, we present the crystal structure of the ecdysone phosphate phosphatase (EPPase) phosphoglycerate mutase (PGM) homology domain, the first structure of a steroid phosphate phosphatase. The structure reveals a α/β-fold common to members of the two histidine (2H)-phosphatase superfamily with strong homology to the suppressor of T-cell receptor signaling-1 (Sts-1 PGM ) protein. The putative EPPase PGM active site contains signature residues shared by 2H-phosphatase enzymes, including a conserved histidine (His80) that acts as a nucleophile during catalysis. The physiological substrate ecdysone 22-phosphate was modeled in a hydrophobic cavity close to the phosphate-binding site. EPPase PGM shows limited substrate specificity with an ability to hydrolyze steroid phosphates, the phospho-tyrosine (pTyr) substrate analogue paranitrophenylphosphate (pNPP) and pTyr-containing peptides and proteins. Altogether, our data demonstrate a new protein tyrosine phosphatase (PTP) activity for EPPase. They suggest that EPPase and its closest homologues can be grouped into a distinct subfamily in the large 2H-phosphatase superfamily of proteins. KeywordsEPPase; ecdysone; E22P; ecdysteroid; phosphatase; phospho-histidine; PTP; Sts-1In invertebrates, the ecdysteroid hormones (ecdysone and its derivatives) regulate the major stages of development including growth, body size, cellular division, programmed cell death, color change, molting and metamorphosis (1-6). They do so by binding to the ecdysone receptor (EcR), a ligand-inducible transcription factor that controls the expression of genes involved in ecdysis and metamorphosis. The important roles of various ecdysteroid hormones *CORRESPONDING AUTHOR Nicolas Nassar, Department of Physiology and Biophysics, Basic Sciences Tower, Stony Brook University, Stony Brook, NY 11794-8661. Tel: 631-444-3521, FAX: 631-444-3432; email: nicolas.nassar@sunysb for embryonic development in insects have been well demonstrated in the eggs of the silkworm Bombyx mori and the fly Drosophila (7). Ecdysone, the prohormone of the major insect molting hormone 20-hydroxyecdysone (20E), is synthesized from cholesterol and controls the timing of molting (8). In particular, analysis of the interaction between the ecdysteroid receptor and various egg ecdysteroids of B. mori suggested that 20E is responsible for the development difference between diapause and non-diapause in B. mori embryos (9). Additionally, recent findings revealed a coordinated crosstalk between the ecdysone and insulin signaling pathways to regulate growth and developmental timing to determine final body size (10-12).In insects, ecdysteroid hormones undergo inactivation by phosphorylation and are stored as physiologically inactive hormones until needed. Recently, an ecdysteroid phosphate phosphatase (EPPase) was identified from B. mori eggs with specificity for ecdysteroid phosphates that have a phosphate group at position 22 on the side chain of the steroid. EPPase converts inactive ecdysteroid phosphate, ecdysone 22-phosphate (E2...

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Section: Resultsmentioning

confidence: 99%

Structural and Functional Characterization of the C-Terminal Domain of the Ecdysteroid Phosphate Phosphatase from Bombyx mori Reveals a New Enzymatic Activity

et al. 2008

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“…Det1 is a soluble cytoplasmic protein and a recent biochemical screen identified it as an acid phosphatase with broad substrate specificity [112]. Interestingly, an ecdysteroid phosphate phosphatase and the related human proteins Sts-1 were recently identified as members of the histidine phosphatase superfamily and shown to have phosphatase activity towards ecdysteroid-and steroid-phosphates [113]. Further studies will be required to examine whether the phosphatase activity of Det1 is important for its function in sterol trafficking.…”

Section: Genetic Screens For Sterol Uptake and Transport Mutantsmentioning

confidence: 98%

Mechanisms of sterol uptake and transport in yeast

Jacquier

Schneiter

2012

The Journal of Steroid Biochemistry and Molecular Biology

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“…Thus, the particular similarity of TULA-family proteins with ecdysone phosphate phosphatase (EPP) [16] argued that TULA might act on phosphorylated steroids. However, while both TULA-2 and EPP demonstrate ability to dephosphorylate phosphorylated steroids, pNpp, and phosphotyrosine-containing peptides/proteins [16,17], TULA shows no activity towards either phosphorylated steroids or multiple other small phosphorylated molecules [11].…”

Section: Very Similar But Considerably Distinctmentioning

confidence: 99%

TULA-family proteins: an odd couple

Tsygankov

2009

Cell. Mol. Life Sci.

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Two members of the TULA family (TULA/STS-2/UBASH3A and TULA-2/STS-1/UBASH3B) recently emerged as novel regulators of several cellular functions. The degree of structural similarity between the TULA-family proteins is typical for proteins that belong to the same family. Furthermore, the experiments with knockout mice lacking these proteins may be interpreted as suggesting that functions of TULA-family proteins in T lymphocytes overlap. At the same time, TULA and TULA-2 exhibit clear functional dissimilarities, starting with the finding that a conserved phosphatase domain present in both proteins exhibits remarkable differences in enzymatic activity; TULA-2 is an active phosphatase capable of dephosphorylating multiple tyrosine-phosphorylated proteins, whereas the phosphatase activity of TULA is extremely low. In contrast, TULA, but not TULA-2, facilitates growth factor withdrawal-induced apoptosis in T cells. In spite of their apparent importance, the functional role of TULA-family proteins is not well understood. In particular, the role of functional dissimilarities between them remains unclear.

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An unsuspected ecdysteroid/steroid phosphatase activity in the key T‐cell regulator, Sts‐1: Surprising relationship to insect ecdysteroid phosphate phosphatase

Cited by 25 publications

References 60 publications

Structural and Functional Characterization of the C-Terminal Domain of the Ecdysteroid Phosphate Phosphatase from Bombyx mori Reveals a New Enzymatic Activity

Structural and Functional Characterization of the C-Terminal Domain of the Ecdysteroid Phosphate Phosphatase from Bombyx mori Reveals a New Enzymatic Activity

Mechanisms of sterol uptake and transport in yeast

TULA-family proteins: an odd couple

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