Structural insights into the homology and differences between mouse protein tyrosine phosphatase-sigma and human protein tyrosine phosphatase-sigma

Li, Hou; Wang, Jianchuan; Zhou, Yuwei; Li, Jingya; Zang, Yi; Li, Jia

doi:10.1093/abbs/gmr095

Cited by 6 publications

(4 citation statements)

References 27 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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“…These results suggest that mPTPRO either does not control Eph activity in the retinocollicular system, or is functionally redundant with other phosphatases that regulate Eph activity (Nievergall et al, 2010). Mouse and chick PTPRO are divergent enough (80% similarity) to have different substrate specificities, as was previously shown for mouse and human RPTPσ (Hou et al, 2011). Future structure-function work to elucidate the molecular basis of substrate specificity of mouse versus chick PTPRO would be interesting to help shed light into this rather unexplored question.…”

Section: Discussionsupporting

confidence: 57%

Protein Tyrosine Phosphatase Receptor Type O Inhibits Trigeminal Axon Growth and Branching by Repressing TrkB and Ret Signaling

et al. 2013

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Axonal branches of the trigeminal ganglion (TG) display characteristic growth and arborization patterns during development. Subsets of TG neurons express different receptors for growth factors, but these are unlikely to explain the unique patterns of axonal arborizations. Intrinsic modulators may restrict or enhance cellular responses to specific ligands and thereby contribute to the development of axon growth patterns. Protein tyrosine phosphatase receptor type O (PTPRO) which is required for Eph receptor-dependent retinotectal development in chick and for development of subsets of trunk sensory neurons in mouse, may be such an intrinsic modulator of TG neuron development. PTPRO is expressed mainly in TrkB+ and Ret+ mechanoreceptors within the TG during embryogenesis. In PTPRO mutant mice, subsets of TG neurons grow longer and more elaborate axonal branches. Cultured PTPRO−/− TG neurons display enhanced axonal outgrowth and branching in response to BDNF and GDNF compared to control neurons, indicating that PTPRO negatively controls the activity of BDNF/TrkB and GDNF/Ret signaling. Mouse PTPRO fails to regulate Eph signaling in retinocollicular development and in hindlimb motor axon guidance, suggesting that chick and mouse PTPRO have different substrate specificities. PTPRO has evolved to fine tune growth factor signaling in a cell type specific fashion and to thereby increase the diversity of signaling output of a limited number of receptor tyrosine kinases to control the branch morphology of developing sensory neurons. The regulation of Eph receptor-mediated developmental processes by protein tyrosine phosphatases has diverged between chick and mouse.

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“…Identification of PTPσ mutations to disrupt specific interactions. (A) Interaction scores for each ligand in the dihydrofolate reductase (DHFR) protein complementation assay mapped onto the PTPσ crystal structure (Hou et al, 2011). Interaction scores are divided into five bins and colored accordingly: <0.2 purple; 0.2–0.4 blue; 0.4–0.6 teal; 0.6–0.8 green; >0.8 yellow.…”

Section: Methodsmentioning

confidence: 99%

Mechanisms of PTPσ-Mediated Presynaptic Differentiation

Bomkamp

Padmanabhan

Karimi

et al. 2019

Front. Synaptic Neurosci.

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Formation of synapses between neurons depends in part on binding between axonal and dendritic cell surface synaptic organizing proteins, which recruit components of the developing presynaptic and postsynaptic specializations. One of these presynaptic organizing molecules is protein tyrosine phosphatase σ (PTPσ). Although the protein domains involved in adhesion between PTPσ and its postsynaptic binding partners are known, the mechanisms by which it signals into the presynaptic neuron to recruit synaptic vesicles and other necessary components for regulated transmitter release are not well understood. One attractive candidate to mediate this function is liprin-α, a scaffolding protein with well-established roles at the synapse. We systematically mutated residues of the PTPσ intracellular region (ICR) and used the yeast dihydrofolate reductase (DHFR) protein complementation assay to screen for disrupted interactions between these mutant forms of PTPσ and its various binding partners. Using a molecular replacement strategy, we show that disrupting the interaction between PTPσ and liprin-α, but not between PTPσ and itself or another binding partner, caskin, abolishes presynaptic differentiation. Furthermore, phosphatase activity of PTPσ and binding to extracellular heparan sulfate (HS) proteoglycans are dispensable for presynaptic induction. Previous reports have suggested that binding between PTPσ and liprin-α is mediated by the PTPσ membrane-distal phosphatase-like domain. However, we provide evidence here that both of the PTPσ phosphatase-like domains mediate binding to liprin-α and are required for PTPσ-mediated presynaptic differentiation. These findings further our understanding of the mechanistic basis by which PTPσ acts as a presynaptic organizer.

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Structural insights into the homology and differences between mouse protein tyrosine phosphatase-sigma and human protein tyrosine phosphatase-sigma

Cited by 6 publications

References 27 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

Protein Tyrosine Phosphatase Receptor Type O Inhibits Trigeminal Axon Growth and Branching by Repressing TrkB and Ret Signaling

Mechanisms of PTPσ-Mediated Presynaptic Differentiation

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