The Experts below are selected from a list of 4875 Experts worldwide ranked by ideXlab platform
Roger W Innes - One of the best experts on this subject based on the ideXlab platform.
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structure function analysis of the coiled coil and leucine rich repeat Domains of the rps5 disease resistance protein
Plant Physiology, 2012Co-Authors: Brody J Deyoung, Roger W InnesAbstract:The Arabidopsis (Arabidopsis thaliana) RESISTANCE TO PSEUDOMONAS SYRINGAE5 (RPS5) disease resistance protein mediates recognition of the Pseudomonas syringae effector protein AvrPphB. RPS5 belongs to the coiled-coil-nucleotide-binding site-leucine-rich repeat (CC-NBS-LRR) family and is activated by AvrPphB-mediated cleavage of the protein kinase PBS1. Here, we present a structure-function analysis of the CC and LRR Domains of RPS5 using transient expression assays in Nicotiana benthamiana. We found that substituting the CC Domain of RPS2 for the RPS5 CC Domain did not alter RPS5 specificity and only moderately reduced its ability to activate programmed cell death, suggesting that the CC Domain does not play a direct role in the recognition of PBS1 cleavage. Analysis of an RPS5-super Yellow Fluorescent Protein fusion revealed that RPS5 localizes to the plasma membrane (PM). Alanine substitutions of predicted myristoylation (glycine-2) and palmitoylation (cysteine-4) residues affected RPS5 PM localization, protein stability, and function in an additive manner, indicating that PM localization is essential to RPS5 function. The first 20 amino acids of RPS5 were sufficient for directing super Yellow Fluorescent Protein to the PM. C-terminal truncations of RPS5 revealed that the first four LRR repeats are sufficient for inhibiting RPS5 autoactivation; however, the complete LRR Domain was required for the recognition of PBS1 cleavage. Substitution of the RPS2 LRR Domain resulted in the autoactivation of RPS5, indicating that the LRR Domain must coevolve with the NBS Domain. We conclude that the RPS5 LRR Domain functions to suppress RPS5 activation in the absence of PBS1 cleavage and promotes RPS5 activation in its presence.
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Structure-Function Analysis of the Coiled-Coil and Leucine-Rich Repeat Domains of the RPS5 Disease
2012Co-Authors: Brody J Deyoung, Roger W InnesAbstract:The Arabidopsis (Arabidopsis thaliana) RESISTANCE TO PSEUDOMONAS SYRINGAE5 (RPS5) disease resistance proteinmediates recognition of the Pseudomonas syringae effector protein AvrPphB. RPS5 belongs to the coiled-coil-nucleotide-bindingsite-leucine-rich repeat (CC-NBS-LRR) family and is activated by AvrPphB-mediated cleavage of the protein kinase PBS1.Here, we present a structure-function analysis of the CC and LRR Domains of RPS5 using transient expression assays inNicotiana benthamiana. We found that substituting the CC Domain of RPS2 for the RPS5 CC Domain did not alter RPS5specificity and only moderately reduced its ability to activate programmed cell death, suggesting that the CC Domain does notplay a direct role in the recognition of PBS1 cleavage. Analysis of an RPS5-super Yellow Fluorescent Protein fusion revealedthat RPS5 localizes to the plasma membrane (PM). Alanine substitutions of predicted myristoylation (glycine-2) andpalmitoylation (cysteine-4) residues affected RPS5 PM localization, protein stability, and function in an additive manner,indicating that PM localization is essential to RPS5 function. The first 20 amino acids of RPS5 were sufficient for directing superYellow Fluorescent Protein to the PM. C-terminal truncations of RPS5 revealed that the first four LRR repeats are sufficient forinhibiting RPS5 autoactivation; however, the complete LRR Domain was required for the recognition of PBS1 cleavage.Substitution of the RPS2 LRR Domain resulted in the autoactivation of RPS5, indicating that the LRR Domain must coevolvewith the NBS Domain. We conclude that the RPS5 LRR Domain functions to suppress RPS5 activation in the absence of PBS1cleavage and promotes RPS5 activation in its presence.
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indirect activation of a plant nucleotide binding site leucine rich repeat protein by a bacterial protease
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Brody J Deyoung, Catherine Golstein, Roger W InnesAbstract:Nucleotide binding site–leucine-rich repeat (NBS–LRR) proteins mediate pathogen recognition in both mammals and plants. The molecular mechanisms by which pathogen molecules activate NBS–LRR proteins are poorly understood. Here we show that RPS5, a NBS–LRR protein from Arabidopsis, is activated by AvrPphB, a bacterial protease, via an indirect mechanism. When transiently expressed in Nicotiana benthamiana leaves, full-length RPS5 protein triggered programmed cell death, but only when coexpressed with AvrPphB and a second Arabidopsis protein, PBS1, which is a specific substrate of AvrPphB. Using coimmunoprecipitation analysis, we found that PBS1 is in a complex with the N-terminal coiled coil (CC) Domain of RPS5 before exposure to AvrPphB. Deletion of the RPS5 LRR Domain caused RPS5 to constitutively activate programmed cell death, even in the absence of AvrPphB and PBS1, and this activation depended on both the CC and NBS Domains. The LRR and CC Domains both coimmunoprecipitate with the NBS Domain but not with each other. Thus, the LRR Domain appears to function in part to inhibit RPS5 signaling, and cleavage of PBS1 by AvrPphB appears to release RPS5 from this inhibition. An amino acid substitution in the NBS site of RPS5 that is known to inhibit ATP binding in other NBS–LRR proteins blocked activation of RPS5, whereas a substitution thought to inhibit ATP hydrolysis constitutively activated RPS5. Combined, these data suggest that ATP versus ADP binding functions as a molecular switch that is flipped by cleavage of PBS1.
Hal M Hoffman - One of the best experts on this subject based on the ideXlab platform.
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role of the leucine rich repeat Domain of cryopyrin nalp3 in monosodium urate crystal induced inflammation in mice
Arthritis & Rheumatism, 2010Co-Authors: Hal M Hoffman, James L Mueller, Peter A. Scott, Amir Misaghi, Sean Stevens, George D. Yancopoulos, Andrew J. Murphy, David M. Valenzuela, Ru LiubryanAbstract:Objective The mechanism by which monosodium urate monohydrate (MSU) crystals intracellularly activate the cryopyrin inflammasome is unknown. The aim of this study was to use a mouse molecular genetics–based approach to test whether the leucine-rich repeat (LRR) Domain of cryopyrin is required for MSU crystal–induced inflammation. Methods Cryopyrin-knockout lacZ (Cryo−Z/−Z) mice and mice with the cryopyrin LRR Domain deleted and fused to the lacZ reporter (CryoΔLRR Z/ΔLRR Z) were generated using bacterial artificial chromosome–based targeting vectors, which allow for large genomic deletions. Bone marrow–derived macrophages from CryoΔLRR Z/ΔLRR Z mice, Cryo−Z/−Z mice, and congenic wild-type (WT) mice were challenged with endotoxin-free MSU crystals under serum-free conditions. Phagocytosis and cytokine expression were assessed by flow cytometry and enzyme-linked immunosorbent assay. MSU crystals also were injected into mouse synovial-like subcutaneous air pouches. The in vivo inflammatory responses were examined. Results Release of interleukin-1β (IL-1β), but not CXCL1 and tumor necrosis factor α, was impaired in CryoΔLRR Z/ΔLRR Z and Cryo−Z/−Z mouse bone marrow–derived macrophages compared with WT mouse bone marrow–derived macrophages in response to not only MSU crystals but also other known stimuli that activate the cryopyrin inflammasome. In addition, a comparable percentage of MSU crystals taken up by each type of bone marrow–derived macrophage was observed. Moreover, total leukocyte infiltration in the air pouch and IL-1β production were attenuated in Cryo−Z/−Z and CryoΔLRR Z/ΔLRR Z mice at 6 hours postinjection of MSU crystals compared with WT mice. Conclusion MSU crystal–induced inflammatory responses were comparably attenuated both in vitro and in vivo in CryoΔLRR Z/ΔLRR Z and Cryo−Z/−Z mice. Hence, the LRR Domain of cryopyrin plays a role in mediating MSU crystal–induced inflammation in this model.
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Role of the leucine-rich repeat Domain of cryopyrin/NALP3 in monosodium urate crystal-induced inflammation in mice.
Arthritis and rheumatism, 2010Co-Authors: Hal M Hoffman, James L Mueller, Peter A. Scott, Amir Misaghi, Sean Stevens, George D. Yancopoulos, Andrew J. Murphy, David M. Valenzuela, Ru Liu-bryanAbstract:Objective The mechanism by which monosodium urate monohydrate (MSU) crystals intracellularly activate the cryopyrin inflammasome is unknown. The aim of this study was to use a mouse molecular genetics–based approach to test whether the leucine-rich repeat (LRR) Domain of cryopyrin is required for MSU crystal–induced inflammation. Methods Cryopyrin-knockout lacZ (Cryo−Z/−Z) mice and mice with the cryopyrin LRR Domain deleted and fused to the lacZ reporter (CryoΔLRR Z/ΔLRR Z) were generated using bacterial artificial chromosome–based targeting vectors, which allow for large genomic deletions. Bone marrow–derived macrophages from CryoΔLRR Z/ΔLRR Z mice, Cryo−Z/−Z mice, and congenic wild-type (WT) mice were challenged with endotoxin-free MSU crystals under serum-free conditions. Phagocytosis and cytokine expression were assessed by flow cytometry and enzyme-linked immunosorbent assay. MSU crystals also were injected into mouse synovial-like subcutaneous air pouches. The in vivo inflammatory responses were examined. Results Release of interleukin-1β (IL-1β), but not CXCL1 and tumor necrosis factor α, was impaired in CryoΔLRR Z/ΔLRR Z and Cryo−Z/−Z mouse bone marrow–derived macrophages compared with WT mouse bone marrow–derived macrophages in response to not only MSU crystals but also other known stimuli that activate the cryopyrin inflammasome. In addition, a comparable percentage of MSU crystals taken up by each type of bone marrow–derived macrophage was observed. Moreover, total leukocyte infiltration in the air pouch and IL-1β production were attenuated in Cryo−Z/−Z and CryoΔLRR Z/ΔLRR Z mice at 6 hours postinjection of MSU crystals compared with WT mice. Conclusion MSU crystal–induced inflammatory responses were comparably attenuated both in vitro and in vivo in CryoΔLRR Z/ΔLRR Z and Cryo−Z/−Z mice. Hence, the LRR Domain of cryopyrin plays a role in mediating MSU crystal–induced inflammation in this model.
Brody J Deyoung - One of the best experts on this subject based on the ideXlab platform.
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structure function analysis of the coiled coil and leucine rich repeat Domains of the rps5 disease resistance protein
Plant Physiology, 2012Co-Authors: Brody J Deyoung, Roger W InnesAbstract:The Arabidopsis (Arabidopsis thaliana) RESISTANCE TO PSEUDOMONAS SYRINGAE5 (RPS5) disease resistance protein mediates recognition of the Pseudomonas syringae effector protein AvrPphB. RPS5 belongs to the coiled-coil-nucleotide-binding site-leucine-rich repeat (CC-NBS-LRR) family and is activated by AvrPphB-mediated cleavage of the protein kinase PBS1. Here, we present a structure-function analysis of the CC and LRR Domains of RPS5 using transient expression assays in Nicotiana benthamiana. We found that substituting the CC Domain of RPS2 for the RPS5 CC Domain did not alter RPS5 specificity and only moderately reduced its ability to activate programmed cell death, suggesting that the CC Domain does not play a direct role in the recognition of PBS1 cleavage. Analysis of an RPS5-super Yellow Fluorescent Protein fusion revealed that RPS5 localizes to the plasma membrane (PM). Alanine substitutions of predicted myristoylation (glycine-2) and palmitoylation (cysteine-4) residues affected RPS5 PM localization, protein stability, and function in an additive manner, indicating that PM localization is essential to RPS5 function. The first 20 amino acids of RPS5 were sufficient for directing super Yellow Fluorescent Protein to the PM. C-terminal truncations of RPS5 revealed that the first four LRR repeats are sufficient for inhibiting RPS5 autoactivation; however, the complete LRR Domain was required for the recognition of PBS1 cleavage. Substitution of the RPS2 LRR Domain resulted in the autoactivation of RPS5, indicating that the LRR Domain must coevolve with the NBS Domain. We conclude that the RPS5 LRR Domain functions to suppress RPS5 activation in the absence of PBS1 cleavage and promotes RPS5 activation in its presence.
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Structure-Function Analysis of the Coiled-Coil and Leucine-Rich Repeat Domains of the RPS5 Disease
2012Co-Authors: Brody J Deyoung, Roger W InnesAbstract:The Arabidopsis (Arabidopsis thaliana) RESISTANCE TO PSEUDOMONAS SYRINGAE5 (RPS5) disease resistance proteinmediates recognition of the Pseudomonas syringae effector protein AvrPphB. RPS5 belongs to the coiled-coil-nucleotide-bindingsite-leucine-rich repeat (CC-NBS-LRR) family and is activated by AvrPphB-mediated cleavage of the protein kinase PBS1.Here, we present a structure-function analysis of the CC and LRR Domains of RPS5 using transient expression assays inNicotiana benthamiana. We found that substituting the CC Domain of RPS2 for the RPS5 CC Domain did not alter RPS5specificity and only moderately reduced its ability to activate programmed cell death, suggesting that the CC Domain does notplay a direct role in the recognition of PBS1 cleavage. Analysis of an RPS5-super Yellow Fluorescent Protein fusion revealedthat RPS5 localizes to the plasma membrane (PM). Alanine substitutions of predicted myristoylation (glycine-2) andpalmitoylation (cysteine-4) residues affected RPS5 PM localization, protein stability, and function in an additive manner,indicating that PM localization is essential to RPS5 function. The first 20 amino acids of RPS5 were sufficient for directing superYellow Fluorescent Protein to the PM. C-terminal truncations of RPS5 revealed that the first four LRR repeats are sufficient forinhibiting RPS5 autoactivation; however, the complete LRR Domain was required for the recognition of PBS1 cleavage.Substitution of the RPS2 LRR Domain resulted in the autoactivation of RPS5, indicating that the LRR Domain must coevolvewith the NBS Domain. We conclude that the RPS5 LRR Domain functions to suppress RPS5 activation in the absence of PBS1cleavage and promotes RPS5 activation in its presence.
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indirect activation of a plant nucleotide binding site leucine rich repeat protein by a bacterial protease
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Brody J Deyoung, Catherine Golstein, Roger W InnesAbstract:Nucleotide binding site–leucine-rich repeat (NBS–LRR) proteins mediate pathogen recognition in both mammals and plants. The molecular mechanisms by which pathogen molecules activate NBS–LRR proteins are poorly understood. Here we show that RPS5, a NBS–LRR protein from Arabidopsis, is activated by AvrPphB, a bacterial protease, via an indirect mechanism. When transiently expressed in Nicotiana benthamiana leaves, full-length RPS5 protein triggered programmed cell death, but only when coexpressed with AvrPphB and a second Arabidopsis protein, PBS1, which is a specific substrate of AvrPphB. Using coimmunoprecipitation analysis, we found that PBS1 is in a complex with the N-terminal coiled coil (CC) Domain of RPS5 before exposure to AvrPphB. Deletion of the RPS5 LRR Domain caused RPS5 to constitutively activate programmed cell death, even in the absence of AvrPphB and PBS1, and this activation depended on both the CC and NBS Domains. The LRR and CC Domains both coimmunoprecipitate with the NBS Domain but not with each other. Thus, the LRR Domain appears to function in part to inhibit RPS5 signaling, and cleavage of PBS1 by AvrPphB appears to release RPS5 from this inhibition. An amino acid substitution in the NBS site of RPS5 that is known to inhibit ATP binding in other NBS–LRR proteins blocked activation of RPS5, whereas a substitution thought to inhibit ATP hydrolysis constitutively activated RPS5. Combined, these data suggest that ATP versus ADP binding functions as a molecular switch that is flipped by cleavage of PBS1.
James L Mueller - One of the best experts on this subject based on the ideXlab platform.
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Alternative splicing regulates stochastic NLRP3 activity.
Nature communications, 2019Co-Authors: Florian Hoss, James L Mueller, Francisca Rojas Ringeling, Juan F. Rodriguez-alcazar, Rebecca Brinkschulte, Gerald Seifert, Rainer Stahl, Lori Broderick, Christopher D. Putnam, Richard D. KolodnerAbstract:Leucine-rich repeat (LRR) Domains are evolutionarily conserved in proteins that function in development and immunity. Here we report strict exonic modularity of LRR Domains of several human gene families, which is a precondition for alternative splicing (AS). We provide evidence for AS of LRR Domain within several Nod-like receptors, most prominently the inflammasome sensor NLRP3. Human NLRP3, but not mouse NLRP3, is expressed as two major isoforms, the full-length variant and a variant lacking exon 5. Moreover, NLRP3 AS is stochastically regulated, with NLRP3 ∆ exon 5 lacking the interaction surface for NEK7 and hence loss of activity. Our data thus reveals unexpected regulatory roles of AS through differential utilization of LRRs modules in vertebrate innate immunity.
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role of the leucine rich repeat Domain of cryopyrin nalp3 in monosodium urate crystal induced inflammation in mice
Arthritis & Rheumatism, 2010Co-Authors: Hal M Hoffman, James L Mueller, Peter A. Scott, Amir Misaghi, Sean Stevens, George D. Yancopoulos, Andrew J. Murphy, David M. Valenzuela, Ru LiubryanAbstract:Objective The mechanism by which monosodium urate monohydrate (MSU) crystals intracellularly activate the cryopyrin inflammasome is unknown. The aim of this study was to use a mouse molecular genetics–based approach to test whether the leucine-rich repeat (LRR) Domain of cryopyrin is required for MSU crystal–induced inflammation. Methods Cryopyrin-knockout lacZ (Cryo−Z/−Z) mice and mice with the cryopyrin LRR Domain deleted and fused to the lacZ reporter (CryoΔLRR Z/ΔLRR Z) were generated using bacterial artificial chromosome–based targeting vectors, which allow for large genomic deletions. Bone marrow–derived macrophages from CryoΔLRR Z/ΔLRR Z mice, Cryo−Z/−Z mice, and congenic wild-type (WT) mice were challenged with endotoxin-free MSU crystals under serum-free conditions. Phagocytosis and cytokine expression were assessed by flow cytometry and enzyme-linked immunosorbent assay. MSU crystals also were injected into mouse synovial-like subcutaneous air pouches. The in vivo inflammatory responses were examined. Results Release of interleukin-1β (IL-1β), but not CXCL1 and tumor necrosis factor α, was impaired in CryoΔLRR Z/ΔLRR Z and Cryo−Z/−Z mouse bone marrow–derived macrophages compared with WT mouse bone marrow–derived macrophages in response to not only MSU crystals but also other known stimuli that activate the cryopyrin inflammasome. In addition, a comparable percentage of MSU crystals taken up by each type of bone marrow–derived macrophage was observed. Moreover, total leukocyte infiltration in the air pouch and IL-1β production were attenuated in Cryo−Z/−Z and CryoΔLRR Z/ΔLRR Z mice at 6 hours postinjection of MSU crystals compared with WT mice. Conclusion MSU crystal–induced inflammatory responses were comparably attenuated both in vitro and in vivo in CryoΔLRR Z/ΔLRR Z and Cryo−Z/−Z mice. Hence, the LRR Domain of cryopyrin plays a role in mediating MSU crystal–induced inflammation in this model.
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Role of the leucine-rich repeat Domain of cryopyrin/NALP3 in monosodium urate crystal-induced inflammation in mice.
Arthritis and rheumatism, 2010Co-Authors: Hal M Hoffman, James L Mueller, Peter A. Scott, Amir Misaghi, Sean Stevens, George D. Yancopoulos, Andrew J. Murphy, David M. Valenzuela, Ru Liu-bryanAbstract:Objective The mechanism by which monosodium urate monohydrate (MSU) crystals intracellularly activate the cryopyrin inflammasome is unknown. The aim of this study was to use a mouse molecular genetics–based approach to test whether the leucine-rich repeat (LRR) Domain of cryopyrin is required for MSU crystal–induced inflammation. Methods Cryopyrin-knockout lacZ (Cryo−Z/−Z) mice and mice with the cryopyrin LRR Domain deleted and fused to the lacZ reporter (CryoΔLRR Z/ΔLRR Z) were generated using bacterial artificial chromosome–based targeting vectors, which allow for large genomic deletions. Bone marrow–derived macrophages from CryoΔLRR Z/ΔLRR Z mice, Cryo−Z/−Z mice, and congenic wild-type (WT) mice were challenged with endotoxin-free MSU crystals under serum-free conditions. Phagocytosis and cytokine expression were assessed by flow cytometry and enzyme-linked immunosorbent assay. MSU crystals also were injected into mouse synovial-like subcutaneous air pouches. The in vivo inflammatory responses were examined. Results Release of interleukin-1β (IL-1β), but not CXCL1 and tumor necrosis factor α, was impaired in CryoΔLRR Z/ΔLRR Z and Cryo−Z/−Z mouse bone marrow–derived macrophages compared with WT mouse bone marrow–derived macrophages in response to not only MSU crystals but also other known stimuli that activate the cryopyrin inflammasome. In addition, a comparable percentage of MSU crystals taken up by each type of bone marrow–derived macrophage was observed. Moreover, total leukocyte infiltration in the air pouch and IL-1β production were attenuated in Cryo−Z/−Z and CryoΔLRR Z/ΔLRR Z mice at 6 hours postinjection of MSU crystals compared with WT mice. Conclusion MSU crystal–induced inflammatory responses were comparably attenuated both in vitro and in vivo in CryoΔLRR Z/ΔLRR Z and Cryo−Z/−Z mice. Hence, the LRR Domain of cryopyrin plays a role in mediating MSU crystal–induced inflammation in this model.
Tommi Kajander - One of the best experts on this subject based on the ideXlab platform.
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The structure of SALM5 suggests a dimeric assembly for the presynaptic RPTP ligand recognition.
Protein engineering design & selection : PEDS, 2018Co-Authors: Sudeep Karki, Prodeep Paudel, Celeste Sele, Alexander V. Shkumatov, Tommi KajanderAbstract:Synaptic adhesion molecules play a crucial role in the regulation of synapse development and maintenance. Recently, several families of leucine-rich repeat (LRR) Domain-containing neuronal adhesion molecules have been characterised, including netrin-G ligands, LRRTMs and the synaptic adhesion-like molecule (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 3.1 A crystal structure of the SALM5 LRR-Ig-Domain construct and biophysical studies that verify the crystallographic results. We show that SALM1, SALM3 and SALM5 form similar dimeric structures, in which the LRR Domains form the dimer interface. Both SALM3 and SALM5 bind to RPTP immunoglobulin Domains with micromolar affinity. SALM3 shows a clear preference for the RPTP ligands with the meB splice insert. Our structural studies and sequence conservation analysis suggests a ligand-binding site and mechanism for RPTP binding via the dimeric LRR Domain region.
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The structure of SALM5 suggests a dimeric assembly for the presynaptic RPTP ligand recognition
2017Co-Authors: Sudeep Karki, Prodeep Paudel, Celeste Sele, Alexander V. Shkumatov, Tommi KajanderAbstract:Synaptic 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 A 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.
