scholarly journals The structure of SALM5 suggests a dimeric assembly for the presynaptic RPTP ligand recognition

2017 ◽  
Author(s):  
Sudeep Karki ◽  
Prodeep Paudel ◽  
Celeste Sele ◽  
Alexander V. Shkumatov ◽  
Tommi Kajander
Keyword(s):  
Ligand Binding ◽  
Adhesion Molecules ◽  
Tyrosine Phosphatase ◽  
Cognitive Disorders ◽  
Autism Spectrum ◽  
Receptor Protein ◽  
Biophysical Studies ◽  
Repeat Domain ◽  
Neuronal Adhesion ◽  
Lrr Domain

ABSTRACTSynaptic adhesion molecules play a crucial role in the regulation of synapse development and maintenance. Recently several families of leucine rich repeat domain containing neuronal adhesion molecules have been characterized, including netrin G-ligands, LRRTMs, and the SALM family proteins. Most of these are expressed at the excitatory glutamatergic synapses, and dysfunctions of these genes are genetically linked with cognitive disorders, such as autism spectrum disorders and schizophrenia. The SALM family proteins SALM3 and SALM5, similar to SLITRKs, have been shown to bind to the presynaptic receptor protein tyrosine phosphatase (RPTP) family ligands. Here we present the 3 Å crystal structure of the SALM5 LRR-Ig domain construct, and biophysical studies that verify the crystallographic results. We show that both SALM3 and SALM5 extracellular domains form similar dimeric structures, in which the LRR domains form the dimer interface. Both proteins bind to the RPTP lg-domains with micromolar affinity. SALM3 shows a clear preference for RPTP-ligands with the meB splice insert. This is in accordance with previous results showing that the LRR domain is also required for the ligand binding. Our structural studies and sequence conservation analysis suggests a ligand binding site and mechanism for RPTP binding via the dimeric LRR domain region.

scholarly journals Structural basis of SALM3 dimerization and synaptic adhesion complex formation with PTPσ

2020 ◽  
Author(s):  
Sudeep Karki ◽  
Alexander V. Shkumatov ◽  
Sungwon Bae ◽  
Jaewon Ko ◽  
Tommi Kajander
Keyword(s):  
Adhesion Molecules ◽  
Synapse Formation ◽  
Mutational Analysis ◽  
Tyrosine Phosphatase ◽  
Complex Structure ◽  
Receptor Protein ◽  
Structural Basis ◽  
Leucine Rich Repeat ◽  
Solution Studies ◽  
Lrr Domain

AbstractSynaptic adhesion molecules play an important role in the formation, maintenance and refinement of neuronal connectivity. Recently, several leucine rich repeat (LRR) domain containing neuronal adhesion molecules have been characterized including netrin G-ligands, SLITRKs and the synaptic adhesion-like molecules (SALMs). Dysregulation of these adhesion molecules have been genetically and functionally linked to various neurological disorders. Here we investigated the molecular structure and mechanism of ligand interactions for the postsynaptic SALM3 adhesion protein with its presynaptic ligand, receptor protein tyrosine phosphatase σ (PTPσ). We solved the crystal structure of the dimerized leucine rich repeat (LRR) domain of SALM3, revealing the conserved structural features and mechanism of dimerization. Furthermore, we determined the complex structure of SALM3 with PTPσ using small angle X-ray scattering, revealing a 2:2 complex similar to that observed for SALM5. Solution studies unraveled additional flexibility for the complex structure, but validated the uniform mode of action for SALM3 and SALM5 to promote synapse formation. The relevance of the key interface residues was further confirmed by mutational analysis with cellular binding assays and artificial synapse formation assays. Collectively, our results suggest that SALM3 dimerization is a pre-requisite for the SALM3-PTPσ complex to exert synaptogenic activity.

scholarly journals Inhibition of Striatal-Enriched Protein Tyrosine Phosphatase (STEP) Activity Reverses Behavioral Deficits in a Rodent Model of Autism

2020 ◽  
Author(s):  
Manavi Chatterjee ◽  
Priya Singh ◽  
Jian Xu ◽  
Paul J. Lombroso ◽  
Pradeep K. Kurup
Keyword(s):  
Synaptic Plasticity ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cognitive Disorders ◽  
Therapeutic Benefit ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Protein Tyrosine ◽  
Protein Levels ◽  
Increased Risk

AbstractAutism spectrum disorders (ASDs) are highly prevalent childhood illnesses characterized by impairments in communication, social behavior, and repetitive behaviors. Studies have found aberrant synaptic plasticity and neuronal connectivity during the early stages of brain development and have suggested that these contribute to an increased risk for ASD. STEP is a protein tyrosine phosphatase that regulates synaptic plasticity and is implicated in several cognitive disorders. Here we test the hypothesis that STEP may contribute to some of the aberrant behaviors present in the VPA-induced mouse model of ASD. In utero VPA exposure of pregnant dams results in autistic-like behavior in the pups, which is associated with a significant increase in the STEP expression in the prefrontal cortex. The elevated STEP protein levels are correlated with increased dephosphorylation of STEP substrates GluN2B, Pyk2 and ERK, suggesting upregulated STEP activity. Moreover, pharmacological inhibition of STEP rescues the sociability, repetitive and abnormal anxiety phenotypes commonly associated with ASD. These data suggest that STEP may play a role in the VPA model of ASD and STEP inhibition may have a potential therapeutic benefit in this model.

scholarly journals Dimerization of Protein Tyrosine Phosphatase σ Governs both Ligand Binding and Isoform Specificity

2006 ◽  
Vol 27 (5) ◽  
pp. 1795-1808 ◽  
Author(s):  
Simon Lee ◽  
Clare Faux ◽  
Jennifer Nixon ◽  
Daniel Alete ◽  
John Chilton ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Receptor Protein ◽  
Protein Tyrosine ◽  
Type Iii ◽  
Amino Terminal ◽  
Fibronectin Type Iii ◽  
Fibronectin Type

ABSTRACT Signaling through receptor protein tyrosine phosphatases (RPTPs) can influence diverse processes, including axon development, lymphocyte activation, and cell motility. The molecular regulation of these enzymes, however, is still poorly understood. In particular, it is not known if, or how, the dimerization state of RPTPs is related to the binding of extracellular ligands. Protein tyrosine phosphatase σ (PTPσ) is an RPTP with major isoforms that differ in their complements of fibronectin type III domains and in their ligand-binding specificities. In this study, we show that PTPσ forms homodimers in the cell, interacting at least in part through the transmembrane region. Using this knowledge, we provide the first evidence that PTPσ ectodomains must be presented as dimers in order to bind heterophilic ligands. We also provide evidence of how alternative use of fibronectin type III domain complements in two major isoforms of PTPσ can alter the ligand binding specificities of PTPσ ectodomains. The data suggest that the alternative domains function largely to change the rotational conformations of the amino-terminal ligand binding sites of the ectodomain dimers, thus imparting novel ligand binding properties. These findings have important implications for our understanding of how heterophilic ligands interact with, and potentially regulate, RPTPs.

scholarly journals Extracellular Matrix Remodeling in the Retina and Optic Nerve of a Novel Glaucoma Mouse Model

Biology ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 169
Author(s):  
Jacqueline Reinhard ◽  
Susanne Wiemann ◽  
Sebastian Hildebrandt ◽  
Andreas Faissner
Keyword(s):  
Extracellular Matrix ◽  
Optic Nerve ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Nerve Fibers ◽  
Receptor Protein ◽  
Mrna Levels ◽  
Protein Tyrosine ◽  
Tenascin C ◽  
Iop Elevation

Glaucoma is a neurodegenerative disease that is characterized by the loss of retinal ganglion cells (RGC) and optic nerve fibers. Increased age and intraocular pressure (IOP) elevation are the main risk factors for developing glaucoma. Mice that are heterozygous (HET) for the mega-karyocyte protein tyrosine phosphatase 2 (PTP-Meg2) show chronic and progressive IOP elevation, severe RGCs loss, and optic nerve damage, and represent a valuable model for IOP-dependent primary open-angle glaucoma (POAG). Previously, evidence accumulated suggesting that glaucomatous neurodegeneration is associated with the extensive remodeling of extracellular matrix (ECM) molecules. Unfortunately, little is known about the exact ECM changes in the glaucomatous retina and optic nerve. Hence, the goal of the present study was to comparatively explore ECM alterations in glaucomatous PTP-Meg2 HET and control wild type (WT) mice. Due to their potential relevance in glaucomatous neurodegeneration, we specifically analyzed the expression pattern of the ECM glycoproteins fibronectin, laminin, tenascin-C, and tenascin-R as well as the proteoglycans aggrecan, brevican, and members of the receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) family. The analyses were carried out in the retina and optic nerve of glaucomatous PTP-Meg2 HET and WT mice using quantitative real-time PCR (RT-qPCR), immunohistochemistry, and Western blot. Interestingly, we observed increased fibronectin and laminin levels in the glaucomatous HET retina and optic nerve compared to the WT group. RT-qPCR analyses of the laminins α4, β2 and γ3 showed an altered isoform-specific regulation in the HET retina and optic nerve. In addition, an upregulation of tenascin-C and its interaction partner RPTPβ/ζ/phosphacan was found in glaucomatous tissue. However, comparable protein and mRNA levels for tenascin-R as well as aggrecan and brevican were observed in both groups. Overall, our study showed a remodeling of various ECM components in the glaucomatous retina and optic nerve of PTP-Meg2 HET mice. This dysregulation could be responsible for pathological processes such as neovascularization, inflammation, and reactive gliosis in glaucomatous neurodegeneration.

scholarly journals The receptor protein tyrosine phosphatase PTPRJ negatively modulates the CD98hc oncoprotein in lung cancer cells

Oncotarget ◽  
2018 ◽  
Vol 9 (34) ◽  
pp. 23334-23348 ◽  
Author(s):  
Sabrina D’Agostino ◽  
Delia Lanzillotta ◽  
Mariaconcetta Varano ◽  
Cirino Botta ◽  
Antonio Baldrini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Lung Cancer Cells ◽  
Receptor Protein ◽  
Protein Tyrosine ◽  
Receptor Protein Tyrosine Phosphatase
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