Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Combined Automated Annotation using Multiple IEA Methods
A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions.
-
A human ectodomain screen followed by SPR detected direct binding of SALM2/LRFN1 to all three LAR-family receptor phosphatases (PTPRD, PTPRF, and PTPRS).
"PHA led us to test binding of all LAR-PTPRs to all SALMs by SPR. With the exception of PTPRF-SALM4, we observed binding of all LAR-PTPRs to all SALMs"
SALM2 associate with AMPA and NMDA receptors
-
Reactome summarizes SALM2 association with AMPA and NMDA receptor subunits and localization at mature excitatory synapses.
"SALM2 coimmunoprecipitates with NMDAR and AMPAR subunits isolated from detergent-solubilized brain (Ko et al. 2006). SALM2 co localizes with both pre- and post-synaptic proteins at excitatory synapses in mature neurons."
SALMs 1-3 bind to PSD-95 family members
-
Reactome summarizes binding of SALM1-3, including SALM2/LRFN1, to PSD-95-family scaffolds.
"SALMs 1-3 interact with the PDZ domain containing proteins PSD 95 (DLG4) and synapse associated protein 97 (SAP97 or DLG1) and SAP102 (DLG3)"
SALMs1-3 bind each other in cis interactions
-
Reactome summarizes cis homo- and heteromeric complex formation among SALM1-3, while noting that the functional consequence remains unresolved.
"SALM1, SALM2, and SALM3 form homo- and heteromeric complexes in a cis manner. These SALMs 1-3 coimmunoprecipitate with each other in extracts from brain. Whether the homo and heteromeric complexes formed between SALMs 1-3 contribute to synapse formation or neurite outgrowth remains to be determined (Seabold et al. 2008)."
SALM synaptic cell adhesion-like molecules regulate the differentiation of excitatory synapses.
-
SALM2 localizes to excitatory rather than inhibitory synaptic sites and organizes postsynaptic scaffold/receptor clustering.
"excitatory, but not inhibitory, synaptic sites. ... Bead-induced direct aggregation of SALM2 results in coclustering of PSD-95 and ... other postsynaptic proteins, including GKAP and AMPA receptors."
-
Bidirectional perturbation of SALM2 abundance supports a role in excitatory-synapse and spine differentiation, with knockdown lowering miniature-EPSC frequency but not amplitude.
"Overexpression of SALM2 ... increases the number of excitatory synapses and dendritic spines. ... Knockdown of ... SALM2 by RNA interference reduces the number of excitatory synapses and ... dendritic spines and the frequency, but not amplitude, of miniature excitatory ... postsynaptic currents."
Comparative analysis of structure, expression and PSD95-binding capacity of Lrfn, a novel family of neuronal transmembrane proteins.
-
LRFN proteins are type-I plasma-membrane glycoproteins with extracellular LRR, Ig-like, and fibronectin-III domains.
"Lrfn proteins share leucine-rich repeat ... (LRR)-immunoglobulin-like (Ig)-fibronectin type III (Fn)-transmembrane domain ... structure ... Lrfn1-5 ... commonly encode glycoproteins spanning the plasma membrane, with their ... N-terminus located on the extracellular side."
-
The Lrfn1 cytoplasmic C terminus binds PSD95 PDZ domains and can recruit PSD95 toward Lrfn-positive cell periphery.
"C-termini of Lrfn1, Lrfn2 and ... Lrfn4 were bound by PDZ domains of postsynaptic protein PSD95, re-distributing ... PSD95 to cell periphery where the Lrfn proteins were detected."
The SALM family of adhesion-like molecules forms heteromeric and homomeric complexes.
-
SALM1-3 form a co-immunoprecipitable complex in rat brain, and heterologous-cell assays detect SALM2-containing homo- and heteromeric complexes.
"SALMs 1-3 strongly co-immunoprecipitated with each other ... In ... heterologous cells transfected with SALMs, co-immunoprecipitation studies showed ... that all five SALMs form heteromeric and homomeric complexes."
-
SALM2 did not mediate trans-cellular SALM-SALM adhesion in this assay, constraining its homomeric/heteromeric associations to cis or same-cell complexes.
"Both SALMs 4 and 5 formed homophilic, but not heterophilic associations, ... whereas no trans associations were formed by the other SALMs."
Synaptic adhesion-like molecules (SALMs) promote neurite outgrowth.
-
SALM2 overexpression in cultured hippocampal neurons promotes neurite outgrowth, while extracellular-LRR antibodies and RNAi reduce SALM-family-dependent outgrowth.
"Over-expression of each SALM resulted in enhanced ... neurite outgrowth ... Neurite outgrowth could be ... reduced by applying antibodies targeting the extracellular leucine rich regions ... of SALMs and with RNAi."
-
SALM2 neurite-outgrowth activity depends on both its C-terminal PDZ-binding region and determinants in its N-terminal extracellular region.
"the C-terminal PDZ binding domains of SALMs 1-3 are required for most ... aspects of neurite outgrowth. In addition, by using a chimera of SALMs 2 and 4, ... we found that the N-terminus is also involved in neurite outgrowth."
Selected SALM (synaptic adhesion-like molecule) family proteins regulate synapse formation.
-
In the heterologous-cell/hippocampal-neuron coculture assay, SALM2 did not induce presynaptic differentiation, unlike SALM3 and SALM5.
"Here we demonstrate that SALM3 and SALM5, but not other members of the SALM family, are capable of inducing excitatory and inhibitory presynaptic differentiation in contacting axons."
Structural basis of trans-synaptic interactions between PTPδ and SALMs for inducing synapse formation.
-
The mouse SALM2 LRR-Ig ectodomain forms a crystallographic 2:2 complex with mouse PTPδ in which SALM2 LRR and Ig regions contact PTPδ Ig2 and Ig3.
"We determined the crystal structures of apo-SALM5 (LRR–Ig), and PTPδ (Ig1–Ig3)–SALM2 (LRR–Ig) and PTPδ (Ig1–Fn1)–SALM5 (LRR–Ig) complexes ... the Ig2 and Ig3 domains of PTPδ sandwiches the Ig domain of SALM2 or SALM5. The Ig2 domain of PTPδ also interacts with the LRR domain of SALM2 or SALM5"
-
SALM2 has an eight-repeat LRR domain and dimerizes to bridge two PTPδ monomers, but this structural complex does not establish a stable obligate complex in cells.
"The LRR domains of SALM2 and SALM5 are composed of eight parallel β-strands flanked by the N- and C-terminal caps. ... Our structures revealed the 2:2 binding mode of PTPδ and SALMs. SALMs form a dimer, which bridges two PTPδ monomers."
-
PTPδ mini-exon A is not required for SALM binding, whereas mini-exon B is preferred but dispensable; the authors could not exclude that the crystallized SALM2-PTPδ arrangement might also occur in cis.
"meA is not involved in the binding between the type-IIa RPTPs and SALMs, whereas the insertion of meB is preferred but dispensable for the binding. ... we cannot exclude the possibility that the present PTPδ–SALM2 and PTPδ–SALM5 structures may also reflect the cis complex formed on the postsynaptic membrane."