Structure of the Catalytic Domain of Protein Tyrosine Phosphatase Sigma in the Sulfenic Acid Form

Jeon, Tae Jin; Chien, Pham Ngoc; Chun, Hyunaee; Ryu, Seong Eon

doi:10.1007/s10059-013-0033-x

Cited by 11 publications

(12 citation statements)

References 37 publications

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“…This phenomenon was observed using both DiF-MUP and MUP as substrates, mirroring what was seen with the corresponding RPTP␣ mutants, albeit with differences, namely a marked decrease and a smaller than expected increase in K m when using MUP and DiFMUP, respectively. Whereas these differences in catalytic parameters are possibly due to electrostatic effects following the loss of a negative charge, the observed behavior of RPTP mutants is in agreement with the close approach between D2 and the PXXP motif in the three available crystal structures of the tandem catalytic domain of RPTP (PDB codes 2FH7, 3SR9, and 4BPC (3,38,39)). Although more subtle than in our RPTP␣ structure, a similar interaction in RPTP occurs between the aromatic ring of Tyr 1522 and the side chains of Glu 1521 in D1 and the side chains of Thr 1876 and Ser 1678 in D2, respectively (3).…”

Section: Rptp␣ Allosteric Regulation By D2 Domainsupporting

confidence: 83%

RPTPα phosphatase activity is allosterically regulated by the membrane-distal catalytic domain

Wen

Yang

Wakabayashi

et al. 2020

Journal of Biological Chemistry

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Receptor-type protein tyrosine phosphatase α (RPTPα) is an important positive regulator of SRC kinase activation and a known promoter of cancer growth, fibrosis, and arthritis. The domain structure of RPTPs comprises an extracellular region, a transmembrane helix, and two tandem intracellular catalytic domains referred to as D1 and D2. The D2 domain of RPTPs is believed to mostly play a regulatory function; however, no regulatory model has been established for RPTPα-D2 or other RPTP-D2 domains. Here, we solved the 1.8 Å resolution crystal structure of the cytoplasmic region of RPTPα, encompassing D1 and D2, trapped in a conformation that revealed a possible mechanism through which D2 can allosterically inhibit D1 activity. Using a D2-truncation RPTPα variant and mutational analysis of the D1/D2 interfaces, we show that D2 inhibits RPTPα phosphatase activity and identified a 405PFTP408 motif in D1 that mediates the inhibitory effect of D2. Expression of the gain-of-function F406A/T407A RPTPα variant in HEK293T cells enhanced SRC activation, supporting the relevance of our proposed D2-mediated regulation mechanism in cell signaling. There is emerging interest in the development of allosteric inhibitors of RPTPs but a scarcity of validated allosteric sites for RPTPs. The results of our study not only shed light on the regulatory role of RPTP-D2 domains, but also provide a potentially useful tool for the discovery of chemical probes targeting RPTPα and other RPTPs.

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Section: Rptp␣ Allosteric Regulation By D2 Domainsupporting

confidence: 83%

RPTPα phosphatase activity is allosterically regulated by the membrane-distal catalytic domain

Wen

Yang

Wakabayashi

et al. 2020

Journal of Biological Chemistry

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“…The two intracellular catalytic domains (D1 and D2) of Ptprs were cloned into a pET28a vector, overexpressed in Escherichia coli BL21 and purified 65 . Enzymatic activity of PTPσ was assayed using a modified version of the Malachite Green Assay 66 and the Tyrosine Phosphatase Assay Kit (Promega Corporation).…”

Section: Methodsmentioning

confidence: 99%

PTPσ inhibitors promote hematopoietic stem cell regeneration

et al. 2019

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Receptor type protein tyrosine phosphatase-sigma (PTPσ) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPσ is also expressed by hematopoietic stem cells (HSCs). Here, we describe small molecule inhibitors of PTPσ that promote HSC regeneration in vivo. Systemic administration of the PTPσ inhibitor, DJ001, or its analog, to irradiated mice promotes HSC regeneration, accelerates hematologic recovery, and improves survival. Similarly, DJ001 administration accelerates hematologic recovery in mice treated with 5-fluorouracil chemotherapy. DJ001 displays high specificity for PTPσ and antagonizes PTPσ via unique non-competitive, allosteric binding. Mechanistically, DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase, RAC1, and induction of BCL-X L . Furthermore, treatment of irradiated human HSCs with DJ001 promotes the regeneration of human HSCs capable of multilineage in vivo repopulation. These studies demonstrate the therapeutic potential of selective, small-molecule PTPσ inhibitors for human hematopoietic regeneration.

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“…These include the protein tyrosine phosphatase sigma [101], SHP1/2 (Src homology region 2 domain-containing phosphatase; also a tyrosine phosphatase) [102–104], and PTEN (phosphatase and tensin homolog; structurally resembles dual specificity protein tyrosine phosphatases) [103]. …”

Section: Redox Regulation Of Signalingmentioning

confidence: 99%

Biological chemistry and functionality of protein sulfenic acids and related thiol modifications

Devarie‐Baez

Lopez

Furdui

2015

Free Radical Research

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Selective modification of proteins at cysteine residues by reactive oxygen, nitrogen or sulfur species formed under physiological and pathological states is emerging as a critical regulator of protein activity impacting cellular function. This review focuses primarily on protein sulfenylation (-SOH), a metastable reversible modification connecting reduced cysteine thiols to many products of cysteine oxidation. An overview is first provided on the chemistry principles underlining synthesis, stability and reactivity of sulfenic acids in model compounds and proteins, followed by a brief description of analytical methods currently employed to characterize these oxidative species. The following chapters present a selection of redox-regulated proteins for which the -SOH formation was experimentally confirmed and linked to protein function. These chapters are organized based on the participation of these proteins in the regulation of signaling, metabolism and epigenetics. The last chapter discusses the therapeutic implications of altered redox microenvironment and protein oxidation in disease.

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Structure of the Catalytic Domain of Protein Tyrosine Phosphatase Sigma in the Sulfenic Acid Form

Cited by 11 publications

References 37 publications

RPTPα phosphatase activity is allosterically regulated by the membrane-distal catalytic domain

RPTPα phosphatase activity is allosterically regulated by the membrane-distal catalytic domain

PTPσ inhibitors promote hematopoietic stem cell regeneration

Biological chemistry and functionality of protein sulfenic acids and related thiol modifications

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