Abstract:Synapse development requires spatiotemporally regulated recruitment of synaptic proteins. In this study, we describe a novel presynaptic mechanism of cis‐regulated oligomerization of adhesion molecules that controls synaptogenesis. We identified synaptic adhesion‐like molecule 1 (SALM1) as a constituent of the proposed presynaptic Munc18/CASK/Mint1/Lin7b organizer complex. SALM1 preferentially localized to presynaptic compartments of excitatory hippocampal neurons. SALM1 depletion in excitatory hippocampal pri… Show more
“…Dimerization of SALMs might be a way of regulation of the function and induction of presynaptic signaling by LAR-RPTPs, as in the case of SALM3 and SALM5 biological function depends on the oligomerization 17 , 18 (see below), and SALM4 regulates the function of SALM3 by cis -inhibition, most likely through heterodimer formation 16 . Function of SALM2 remains unclear, but it appears to be able to bind the LAR-RPTP receptors 18 , whereas the function of SALM1 appears quite different, with reported involvement in actin mediated post-synaptic neurexin clustering, and no synapse formation activity reported 30 . Figure 2 The dimer interface of SALM3 LRR domain.…”
Synaptic 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 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 prerequisite for the SALM3-PTPσ complex to exert synaptogenic activity. Neurons form highly complex networks of specific connection patterns through the cellular junctions at synapses. Synaptic adhesion molecules are emerging synapse organizers, which are localized at the nerve cell membranes at the synaptic cleft, and play a crucial role in the formation, maintenance and refinement of neural circuits 1. Several families of synaptic adhesion molecules have been identified, including e.g. neurexins 2 , neuroligins 3 , synaptic adhesion like molecules (SALMs) 4 , leucine-rich repeat (LRR) transmembrane neuronal proteins (LRRTMs) 5 , leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) 6 and netrin-G ligands (NGLs) 7. The dysfunction of synaptic adhesion molecules have been proposed to be involved in onset and progression of various neurological disorders, which includes autism spectrum disorders, schizophrenia and Alzheimer's disease 8-11. The SALM family of proteins also known as LRR and fibronectin III domain containing proteins (LRFNs), represent a family of LRR-containing synaptic adhesion molecules, with five known members (SALM1-SALM5) 4. All the SALM proteins share a similar domain architecture consisting of an extracellular region with an LRR domain, an immunoglobulin (Ig) domain and a fibronectin III (FnIII) domain followed by a transmembrane domain (TM) and a non-structured cytoplasmic region 12. Notably, SALM1-3 contain type I PDZ binding motifs, which are absent in SALM4 and SALM5 4,12 (Fig. 1a). SALMs are considered to be postsynaptic adhesion proteins, mostly expressed in the neurons and regulate neurite outgrowth and branching 12. In addition, they ...
“…Dimerization of SALMs might be a way of regulation of the function and induction of presynaptic signaling by LAR-RPTPs, as in the case of SALM3 and SALM5 biological function depends on the oligomerization 17 , 18 (see below), and SALM4 regulates the function of SALM3 by cis -inhibition, most likely through heterodimer formation 16 . Function of SALM2 remains unclear, but it appears to be able to bind the LAR-RPTP receptors 18 , whereas the function of SALM1 appears quite different, with reported involvement in actin mediated post-synaptic neurexin clustering, and no synapse formation activity reported 30 . Figure 2 The dimer interface of SALM3 LRR domain.…”
Synaptic 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 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 prerequisite for the SALM3-PTPσ complex to exert synaptogenic activity. Neurons form highly complex networks of specific connection patterns through the cellular junctions at synapses. Synaptic adhesion molecules are emerging synapse organizers, which are localized at the nerve cell membranes at the synaptic cleft, and play a crucial role in the formation, maintenance and refinement of neural circuits 1. Several families of synaptic adhesion molecules have been identified, including e.g. neurexins 2 , neuroligins 3 , synaptic adhesion like molecules (SALMs) 4 , leucine-rich repeat (LRR) transmembrane neuronal proteins (LRRTMs) 5 , leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) 6 and netrin-G ligands (NGLs) 7. The dysfunction of synaptic adhesion molecules have been proposed to be involved in onset and progression of various neurological disorders, which includes autism spectrum disorders, schizophrenia and Alzheimer's disease 8-11. The SALM family of proteins also known as LRR and fibronectin III domain containing proteins (LRFNs), represent a family of LRR-containing synaptic adhesion molecules, with five known members (SALM1-SALM5) 4. All the SALM proteins share a similar domain architecture consisting of an extracellular region with an LRR domain, an immunoglobulin (Ig) domain and a fibronectin III (FnIII) domain followed by a transmembrane domain (TM) and a non-structured cytoplasmic region 12. Notably, SALM1-3 contain type I PDZ binding motifs, which are absent in SALM4 and SALM5 4,12 (Fig. 1a). SALMs are considered to be postsynaptic adhesion proteins, mostly expressed in the neurons and regulate neurite outgrowth and branching 12. In addition, they ...
“…However, using unbiased proteomics and biochemical validation coupled with in cellulo and ex vivo analysis we have presented evidence consistent with SNX27 regulating the surface expression and activity of AMPA receptors through association with the synaptic adhesion protein LRFN2 (Figure 8). LRFN2 belongs to the LRFN family, also known as synaptic adhesion-like molecules (SALMs), and whilst these proteins have been associated with inhibitory synapses and at the pre-synapse (Brouwer et al, 2019), their function has principally been linked with excitatory synapses (Ko et al, 2006, Morimura et al, 2006, Wang et al, 2006, Lie et al, 2018, Mah et al, 2010, Loh et al, 2016. In proposing LRFN2 as an accessory protein in the dynamic AMPA receptor trafficking code (Diering and Huganir, 2018), our data adds to the complex regulation of AMPA receptor-mediated synaptic transmission and plasticity.…”
The endosome-associated cargo adaptor sorting nexin-27 (SNX27) is linked to various neuropathologies through sorting of integral proteins to the synaptic surface, most notably AMPA receptors. To provide a broader view of SNX27-associated pathologies we performed proteomics in rat primary neurons to identify SNX27-dependent cargoes, and identified proteins linked to excitotoxicity, epilepsy, intellectual disabilities and working memory deficits. Focusing on the synaptic adhesion molecule LRFN2, we established that SNX27 binds to LRFN2 and regulates its endosomal sorting. Furthermore, LRFN2 associates with AMPA receptors and knockdown of LRFN2 results in decreased surface AMPA receptor expression, reduced synaptic activity, and attenuated hippocampal long-term potentiation. Overall, our study provides an additional mechanism by which SNX27 can control AMPA receptor-mediated synaptic transmission and plasticity indirectly through the sorting of LRFN2 and offers molecular insight into the perturbed function of SNX27 and LRFN2 in a range of neurological conditions.
“…Thus, we conclude that the dimerization mechanism through the LRR domains is conserved in the family, generating a unique dimeric post-synaptic LAR-RPTP ligand, 16 . Function of SALM2 remains unclear, but it appears to be able to bind the LAR-RPTP receptors 18 , whereas the function of SALM1 appears quite different, with reported involvement in actin mediated post-synaptic neurexin clustering, and no synapse formation activity reported 28 .…”
Section: Dimerization Through the Lrr Domain Is A Defining Feature Ofmentioning
confidence: 98%
“…Thus, we conclude that the dimerization mechanism through the LRR domains is conserved in the family, generating a unique dimeric post-synaptic 17,19 (see below), and SALM4 regulates the function of SALM3 by cis-inhibition, most likely through heterodimer formation 16 . Function of SALM2 remains unclear, but it appears to be able to bind the LAR-RPTP receptors 18 , whereas the function of SALM1 appears quite different, with reported involvement in actin mediated post-synaptic neurexin clustering, and no synapse formation activity reported 28 , and has much lower affinity (with K d ca. 50 μM) in vitro for the PTPσ (SK and TK, unpublished observations).…”
Section: Dimerization Through the Lrr Domain Is A Defining Feature Ofmentioning
Synaptic 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.
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