SALM protein interactions at the synapse (Homo sapiens)

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2, 9, 1043, 66, 118117215cytosolGRIN2B L-Glu PSD-95 SALM4:FLOT1(FLOT2)FLOT1 SALM1 SALM2 SALM3 FLOT1(FLOT2)PSD-95 SALM5 SALM1 DLG3 GRIN2D SALM3,SALM5:PSD-95GRIN1 GRIN1 SALM4 PTPRS NMDAR:PSD-95SALM4 PTPRF SALM2,3(SALM1,4)Gly GRIN2A SALM4GRIN2A SALM1 GRIN2B FLOT2 SALM2 FLOT1 GRIN2D GRIN2A GRIN2D GRIN2B NMDA receptorcomplexSALM3 GRIN1 SALM3 L-Glu SALM1,2,3 dimerGRIN2B Gly SALM1,2,3GRIN2C PSD-95SALM3 GRIN2D RTN3 RTN3SALM3GRIN2A Gly SALM1 GRIN2D SALM2:AMPA, NMDAreceptorsL-Glu SALM3:LAR-RPTPsCa permeable AMPA receptors GRIN1 Gly GRIN2A L-Glu PSD-95 GRIN2C AMPA, NMDA receptorsGRIN2C PTPRF PSD-95 DLG1 SALM1 SALM2 PTPRD PSD-95 L-Glu SALM2SALM4 SALM2 SALM1FLOT2 GRIN2C LAR,PTPRS,PTPRDSALM1:NMDAR:PSD-95Ca permeable AMPA receptors SALM2,3(SALM1,4):RTN3PTPRS SALM3 DLG1 SALM3,SALM5SALM2 GRIN2B synapse-associatedproteins (SAP)DLG3 GRIN1 Gly SALM1 PTPRD SALM3 GRIN2C SALM1:SAP proteinsSALM5 SALM3


Description

Recruitment of receptors and ion channels to the postsynaptic membrane is the last step in synapse formation. Many of these proteins interact directly or indirectly with postsynaptic density-95 (PSD95)/Discs large/zona occludens-1 (PDZ) proteins, thus linking them to the postsynaptic scaffold and providing a mechanism for both retaining the protein at the synapse and keeping its proximity to signaling molecules known to associate with PDZ proteins (Nourry et al. 2003, Kim & Sheng 2004, Montgomery et al. 2004, Sheng and Kim 2011). The synaptic adhesion-like molecules (SALM) family belongs to the superfamily of leucine-rich repeat (LRR)-containing adhesion molecules, alternatively referred as LRFN (leucine-rich repeat and fibronectin III domain-containing) is an synapse adhesion molecule linked to NMDA and AMPA receptors. It includes five known members (SALMs 1-5 or LRFN1-5), which have been implicated in the regulation of neurite outgrowth and branching, and synapse formation and maturation. SLAM proteins are distributed to both dendrites and axons in neurons (Ko et al. 2006, Wang et al. 2006, Morimura et al. 2006, Nam ett al. 2011). The family members, SALM1-SALM5, have a single transmembrane (TM) domain and contain extracellular leucine-rich repeats, an Ig C2 type domain, a fibronectin type III domain, and an intracellular postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1 (PDZ) binding domain, which is present on all members except SALM4 and SALM5. View original pathway at:Reactome.

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Bibliography

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  1. Mah W, Ko J, Nam J, Han K, Chung WS, Kim E.; ''Selected SALM (synaptic adhesion-like molecule) family proteins regulate synapse formation.''; PubMed Europe PMC
  2. Ko J, Kim S, Chung HS, Kim K, Han K, Kim H, Jun H, Kaang BK, Kim E.; ''SALM synaptic cell adhesion-like molecules regulate the differentiation of excitatory synapses.''; PubMed Europe PMC
  3. Niethammer M, Kim E, Sheng M.; ''Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases.''; PubMed Europe PMC
  4. Chang K, Seabold GK, Wang CY, Wenthold RJ.; ''Reticulon 3 is an interacting partner of the SALM family of adhesion molecules.''; PubMed Europe PMC
  5. Seabold GK, Wang PY, Chang K, Wang CY, Wang YX, Petralia RS, Wenthold RJ.; ''The SALM family of adhesion-like molecules forms heteromeric and homomeric complexes.''; PubMed Europe PMC
  6. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH.; ''Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95.''; PubMed Europe PMC
  7. Li Y, Zhang P, Choi TY, Park SK, Park H, Lee EJ, Lee D, Roh JD, Mah W, Kim R, Kim Y, Kwon H, Bae YC, Choi SY, Craig AM, Kim E.; ''Splicing-Dependent Trans-synaptic SALM3-LAR-RPTP Interactions Regulate Excitatory Synapse Development and Locomotion.''; PubMed Europe PMC
  8. Swanwick CC, Shapiro ME, Vicini S, Wenthold RJ.; ''Flotillin-1 mediates neurite branching induced by synaptic adhesion-like molecule 4 in hippocampal neurons.''; PubMed Europe PMC
  9. Nam J, Mah W, Kim E.; ''The SALM/Lrfn family of leucine-rich repeat-containing cell adhesion molecules.''; PubMed Europe PMC
  10. Sheng M, Kim E.; ''The postsynaptic organization of synapses.''; PubMed Europe PMC
  11. Wang CY, Chang K, Petralia RS, Wang YX, Seabold GK, Wenthold RJ.; ''A novel family of adhesion-like molecules that interacts with the NMDA receptor.''; PubMed Europe PMC

History

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86498view09:19, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AMPA, NMDA receptorsComplexR-HSA-8849876 (Reactome)
Ca permeable AMPA receptors R-HSA-399714 (Reactome)
DLG1 ProteinQ12959 (Uniprot-TrEMBL)
DLG3 ProteinQ92796 (Uniprot-TrEMBL)
FLOT1 ProteinO75955 (Uniprot-TrEMBL)
FLOT1(FLOT2)ComplexR-HSA-8849894 (Reactome)
FLOT2 ProteinQ14254 (Uniprot-TrEMBL)
GRIN1 ProteinQ05586 (Uniprot-TrEMBL)
GRIN2A ProteinQ12879 (Uniprot-TrEMBL)
GRIN2B ProteinQ13224 (Uniprot-TrEMBL)
GRIN2C ProteinQ14957 (Uniprot-TrEMBL)
GRIN2D ProteinO15399 (Uniprot-TrEMBL)
Gly MetaboliteCHEBI:15428 (ChEBI)
L-Glu MetaboliteCHEBI:16015 (ChEBI)
LAR,PTPRS,PTPRDComplexR-HSA-6798238 (Reactome)
NMDA receptor complexComplexR-HSA-8849905 (Reactome)
NMDAR:PSD-95ComplexR-HSA-8849869 (Reactome)
PSD-95 ProteinP78352 (Uniprot-TrEMBL)
PSD-95ProteinP78352 (Uniprot-TrEMBL)
PTPRD ProteinP23468 (Uniprot-TrEMBL)
PTPRF ProteinP10586 (Uniprot-TrEMBL)
PTPRS ProteinQ13332 (Uniprot-TrEMBL)
RTN3 ProteinO95197 (Uniprot-TrEMBL)
RTN3ProteinO95197 (Uniprot-TrEMBL)
SALM1 ProteinQ9ULH4 (Uniprot-TrEMBL)
SALM1,2,3 dimerComplexR-HSA-8849910 (Reactome)
SALM1,2,3ComplexR-HSA-204742 (Reactome)
SALM1:NMDAR:PSD-95ComplexR-HSA-8849935 (Reactome)
SALM1:SAP proteinsComplexR-HSA-8849913 (Reactome)
SALM1ProteinQ9ULH4 (Uniprot-TrEMBL)
SALM2 ProteinQ9P244 (Uniprot-TrEMBL)
SALM2,3(SALM1,4):RTN3ComplexR-HSA-8849893 (Reactome)
SALM2,3(SALM1,4)ComplexR-HSA-8849896 (Reactome)
SALM2:AMPA, NMDA receptorsComplexR-HSA-8849914 (Reactome)
SALM2ProteinQ9P244 (Uniprot-TrEMBL)
SALM3 ProteinQ6PJG9 (Uniprot-TrEMBL)
SALM3,SALM5:PSD-95ComplexR-HSA-8849899 (Reactome)
SALM3,SALM5ComplexR-HSA-8849939 (Reactome)
SALM3:LAR-RPTPsComplexR-HSA-8855645 (Reactome)
SALM3ProteinQ6PJG9 (Uniprot-TrEMBL)
SALM4 ProteinQ9BTN0 (Uniprot-TrEMBL)
SALM4:FLOT1(FLOT2)ComplexR-HSA-8849870 (Reactome)
SALM4ProteinQ9BTN0 (Uniprot-TrEMBL)
SALM5 ProteinQ96NI6 (Uniprot-TrEMBL)
synapse-associated proteins (SAP)ComplexR-HSA-376003 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AMPA, NMDA receptorsR-HSA-8849881 (Reactome)
FLOT1(FLOT2)R-HSA-8849908 (Reactome)
LAR,PTPRS,PTPRDR-HSA-8855648 (Reactome)
NMDA receptor complexR-HSA-8849878 (Reactome)
NMDAR:PSD-95ArrowR-HSA-8849878 (Reactome)
NMDAR:PSD-95R-HSA-8849906 (Reactome)
PSD-95R-HSA-8849878 (Reactome)
PSD-95R-HSA-8849926 (Reactome)
R-HSA-8849878 (Reactome) Many membrane proteins that contain a PDZ-binding domain require an interaction with a PDZ protein for correct targeting to the cell surface. N-methyl-D-aspartate (NMDA) receptor interact with postsynaptic density protein (PSD-95) and PSD-95 family might serve to anchor NMDA receptors to the submembrane cytoskeleton and aid in the assembly of signal transduction complexes at postsynaptic sites (Niethammer et al. 1996, Kornau et al. 1995).
R-HSA-8849881 (Reactome) SALM2 co-localizes with both pre- and post-synaptic proteins at excitatory synapses in mature neurons. SALM2 associates with AMPA receptors and, to a lesser extent, with NMDA receptors. SALM2 appears to promote the maturation, but not the formation, of excitatory synapses, in line with the fact that synaptic localization of AMPA receptors occurs at late stages of excitatory synaptic development (Ko et al. 2006, Nam et al. 2011).
R-HSA-8849882 (Reactome) In the brain, reticulon 3 (RTN3) tightly associates with SALM2 and SALM3 to form a complex, and interacts relatively weakly with SALM1 and SALM4. This interaction is mediated by the LRR domian in SALMs (Chang et al. 2010).
R-HSA-8849891 (Reactome) SALM1 interacts with the PDZ domain containing proteins PSD-95 (Disks large homolog 4, DLG4), synapse associated protein 97 (SAP97 or DLG1) and SAP102 (DLG3) based on coimmunoprecipitation of detergent-solubilized brain. PDZ proteins play a central role in organizing functionally diverse membrane proteins at the synapse (Wang et al. 2006).
R-HSA-8849900 (Reactome) 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 detrmined (Seabold et al. 2008).
R-HSA-8849906 (Reactome) SALM1 interacts with and recruits NMDA receptors to early synapses. NMDA receptors are involved in the development of excitatory synapse by interacting with PDZ proteins of the PSD-95 family through its NR2 subunits. SALM1 can directly interact with the extracellular domain of the NR1 subunit of NMDA receptor or indirectly by binding to PSD-95 which may recruit NMDA receptor via the NR2 subunits of NMDA receptors (Wang et al. 2006, Niethammer et al. 1996, Kornau et al. 1995).
R-HSA-8849908 (Reactome) SALM4 induces neurite branching by binding to flotillin-1, a lipid raft-associated protein that interacts with NMDA receptors (Swanwick et al. 2009, 2010).
R-HSA-8849926 (Reactome) SALM3 and SALM5 proteins are enriched in synaptic fractions, and form strong (SALM3) or weak (SALM5) complexes with postsynaptic density-95 (PSD-95), an abundant postsynaptic scaffolding protein at excitatory synapses. SALM3 and SALM5, but not other SALMs, induce presynaptic differentiation in contacting axons (Mah et al. 2010).
R-HSA-8855648 (Reactome) SALM3 interacts with LAR family receptor protein tyrosine phosphatases (LAR-RPTPs) in a manner requiring the mini-exon B splice insert in LAR-RPTPs (Li et al. 2015). SALM3-dependent presynaptic differentiation requires all three types of LAR-RPTPs. In support of the in vivo functions of these interactions, SALM3 mutant (Salm3(-/-)) mice display markedly reduced excitatory synapse number but normal synaptic plasticity in the hippocampal CA1 region.
RTN3R-HSA-8849882 (Reactome)
SALM1,2,3 dimerArrowR-HSA-8849900 (Reactome)
SALM1,2,3R-HSA-8849900 (Reactome)
SALM1:NMDAR:PSD-95ArrowR-HSA-8849906 (Reactome)
SALM1:SAP proteinsArrowR-HSA-8849891 (Reactome)
SALM1R-HSA-8849891 (Reactome)
SALM1R-HSA-8849906 (Reactome)
SALM2,3(SALM1,4):RTN3ArrowR-HSA-8849882 (Reactome)
SALM2,3(SALM1,4)R-HSA-8849882 (Reactome)
SALM2:AMPA, NMDA receptorsArrowR-HSA-8849881 (Reactome)
SALM2R-HSA-8849881 (Reactome)
SALM3,SALM5:PSD-95ArrowR-HSA-8849926 (Reactome)
SALM3,SALM5R-HSA-8849926 (Reactome)
SALM3:LAR-RPTPsArrowR-HSA-8855648 (Reactome)
SALM3R-HSA-8855648 (Reactome)
SALM4:FLOT1(FLOT2)ArrowR-HSA-8849908 (Reactome)
SALM4R-HSA-8849908 (Reactome)
synapse-associated proteins (SAP)R-HSA-8849891 (Reactome)
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