Neurexin-centred trans-synaptic adhesion complexes

Neurexins are presynaptic type I transmembrane proteins that act as a hub for trans-synaptic adhesion. Their extracellular LNS domains bind a set of structurally unrelated postsynaptic or secreted partners, forming protein bridges that span the synaptic cleft, hold the pre- and postsynaptic membranes together, and signal in both directions to organize synaptic properties. The best-established partners are the neuroligins, which are catalytically inactive esterase-fold transmembrane proteins; the leucine-rich-repeat LRRTM proteins; and a tripartite bridge in which secreted cerebellin hexamers link neurexin to the amino-terminal domain of delta-family ionotropic glutamate receptors (GluD1/GluD2). Which partner a neurexin engages is controlled in large part by alternative splicing, notably at neurexin splice site 4. OUT OF SCOPE: the intracellular scaffolds recruited by the neurexin and partner cytoplasmic tails (CASK, Mint, PSD-95, gephyrin), the synaptic vesicle release machinery, and the many other neurexin ligands (dystroglycan, neurexophilins, latrophilins, calsyntenins, GABA-A receptor, cerebellin-independent C1q-like proteins). Each of these can be added as further partner variants or as a separate module.

MODULE:neurexin_transsynaptic_adhesionDRAFTBiological Processmodules/neurexin_transsynaptic_adhesion.yaml
synaptic membrane adhesionGO:0099560 trans-synaptic signaling by trans-synaptic complexGO:0099545
PMID:18923512
Neuroligins and neurexins link synaptic function to cognitive disease.
Review establishing neurexins and neuroligins as synaptic cell-adhesion molecules bridging pre- and postsynaptic neurons.
Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse
PMID:20064387
LRRTM2 functions as a neurexin ligand in promoting excitatory synapse formation.
Establishes that structurally unrelated postsynaptic partners converge on neurexin as a common presynaptic receptor, which is the organizing principle of this module.
two unrelated postsynaptic cell-adhesion molecules, LRRTMs and neuroligins, unexpectedly bind to neurexins as the same presynaptic receptor
GO:0099560
synaptic membrane adhesion
The module is grounded in the GO process describing adhesion between the pre- and postsynaptic membranes.
PANTHER:PTN002227321
PAINT node PTN002227321 for the neurexin clade
Local PAINT IBD node in PTHR15036 (taxon Bilateria, NCBITaxon:33213) seeded by NRXN1/NRXN2/NRXN3 and fly and mouse orthologs, with propagated terms F:GO:0097109, F:GO:0004888, C:GO:0098820, C:GO:0048787, P:GO:0097116, P:GO:0007612, P:GO:0030534.

Hub-and-partner module. The neurexin hub is the one required part; the postsynaptic side is modelled as a ONE_OR_MORE variant set because a single neurexin population can engage several partner classes, with alternative splicing (neurexin SS4, neuroligin splice site B) biasing the choice. The neurexin hub is anchored to the bilaterian PAINT node PTN002227321; the neuroligin partner is also bilaterian, whereas the LRRTM and cerebellin-GluD partners are documented in vertebrates. No PANTHER id is asserted for the LRRTM partner: UniProt cross-references LRRTM2 to PTHR45842, whereas PANTHER's own classification places it in PTHR45712:SF19, an LRRTM2-only subfamily of a broad leucine-rich-repeat family, so neither id cleanly names the LRRTM family. Molecular functions for the cerebellin and GluD annotons follow GOA (CBLN1 contributes_to GO:0030545, IDA PMID:27418511) and the completed GRID1 gene review. Only GRID1 has a gene review among the grounded members; NRXN1-3, NLGN1-4, LRRTM2, CBLN1 and GRID2 are not yet reviewed.

6Nodes
2Parts
1Variant Sets
3Variants
5Annotons
1Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:neurexin_transsynaptic_adhesion deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

3 gene-function check(s) reflected in core functions · 0 conflict(s) · 11 evidence or coverage gap(s) (14 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
neurexin_adhesion_activity NRXN1 (human)
UniProtKB:Q9ULB1
Family Representative 		cell-cell adhesion mediator activity
GO:0098632 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
neurexin_adhesion_activity NRXN2 (human)
UniProtKB:Q9P2S2
Family Representative 		cell-cell adhesion mediator activity
GO:0098632 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
neurexin_adhesion_activity NRXN3 (human)
UniProtKB:Q9Y4C0
Family Representative 		cell-cell adhesion mediator activity
GO:0098632 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
neuroligin_activity NLGN1 (human)
UniProtKB:Q8N2Q7
Family Representative 		neurexin family protein binding
GO:0042043 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
neuroligin_activity NLGN2 (human)
UniProtKB:Q8NFZ4
Family Representative 		neurexin family protein binding
GO:0042043 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
lrrtm_activity LRRTM2 (human)
UniProtKB:O43300
Family Representative 		neurexin family protein binding
GO:0042043 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
cerebellin_activity CBLN1 (human)
UniProtKB:P23435
Family Representative 		signaling receptor regulator activity
GO:0030545 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
gluD_activity GRID1 (human)
UniProtKB:Q9ULK0
Family Representative 		signaling receptor regulator activity
GO:0030545 		Contributes Only
The review records contribution to this activity, not independent enabling. Check whether the module participant should be a complex.
gluD_activity GRID2 (human)
UniProtKB:O43424
Family Representative 		signaling receptor regulator activity
GO:0030545 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
neurexin_adhesion_activity Neurexin family
PANTHER:PTHR15036
Family 		cell-cell adhesion mediator activity
GO:0098632 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR15036.
neuroligin_activity Neuroligin family
PANTHER:PTHR43903
Family 		neurexin family protein binding
GO:0042043 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR43903.
lrrtm_activity LRRTM family (leucine-rich repeat transmembrane neuronal proteins)
Family 		neurexin family protein binding
GO:0042043 		Family Id Missing
The family has no identifier linking it to a curated family review.
cerebellin_activity Cerebellin family
PANTHER:PTHR22923
Family 		signaling receptor regulator activity
GO:0030545 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR22923.
gluD_activity Delta-family ionotropic glutamate receptors (GluD1/GluD2)
PANTHER:PTHR18966
Family 		signaling receptor regulator activity
GO:0030545 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR18966.

Gene-review completeness (4/9 grounded genes reviewed)

3 complete review(s) · 2 with deep research · 5 missing review · 2 reviewed but lacking deep research

Gene Review Complete Deep research
GRID1 Q9ULK0 ✓ 46/49 ✗
NRXN1 Q9ULB1 ✓ ✓ ✓
NRXN2 Q9P2S2 ✓ ✓ ✓
NRXN3 Q9Y4C0 ✓ ✓ ✗
LRRTM2 (human) O43300 ✗ — —
GRID2 (human) O43424 ✗ — —
CBLN1 (human) P23435 ✗ — —
NLGN1 (human) Q8N2Q7 ✗ — —
NLGN2 (human) Q8NFZ4 ✗ — —

Details

Context
BilateriaNCBITaxon:33213
synapseGO:0045202
Neurexin-centred trans-synaptic adhesion complexesBiological Processneurexin_transsynaptic_adhesion
synaptic membrane adhesionGO:0099560 trans-synaptic signaling by trans-synaptic complexGO:0099545
Context
BilateriaNCBITaxon:33213
synapseGO:0045202

Connections

Neurexin engagement of a postsynaptic or cleft partner forms the trans-synaptic bridge and initiates bidirectional synapse-organizing signalling.
Part 1: presynaptic neurexin hub
Presynaptic neurexinModuleneurexin_hub

Annotons

Neurexin (NRXN1/2/3): presynaptic trans-synaptic adhesion receptor
neurexin_adhesion_activity
Participant: Family: Neurexin family
Family:
Neurexin familyPANTHER:PTHR15036 PTHR15036 is a broad LNS-domain family that also contains pikachurin and other laminin-G proteins; the neurexin role is carried by the neurexin subfamilies (e.g. PTHR15036:SF51, SF52, SF57) descending from PAINT node PTN002227321.
Representative Members: NRXN1 (human)UniProtKB:Q9ULB1 NRXN2 (human)UniProtKB:Q9P2S2 NRXN3 (human)UniProtKB:Q9Y4C0

Function

cell-cell adhesion mediator activityGO:0098632

Processes

synaptic membrane adhesionGO:0099560

Locations

presynaptic membraneGO:0042734

Presynaptic transmembrane receptor whose extracellular LNS domains bind each of the postsynaptic partner classes below. Alpha- and beta-neurexin isoforms and splice site 4 inserts determine which partners bind: neuroligins bind neurexins with or without the SS4 insert, LRRTM2 only SS4-lacking neurexins, and cerebellin preferentially SS4-containing neurexins.

Part 2: postsynaptic or cleft partner
Neurexin partner classesModuleneurexin_partners
Variant set: Neurexin partner class by partner molecule class (One Or More)

Partner classes are not mutually exclusive; a given synapse can use several, and neurexin and partner alternative splicing bias which bridge forms.

Neurexin-neuroligin bridgeProtein Complexneuroligin_bridge

Annotons

Neuroligin (NLGN1-4): postsynaptic neurexin ligand
neuroligin_activity
Participant: Family: Neuroligin family
Family:
Neuroligin familyPANTHER:PTHR43903
Representative Members: NLGN1 (human)UniProtKB:Q8N2Q7 NLGN2 (human)UniProtKB:Q8NFZ4

Function

neurexin family protein bindingGO:0042043

Locations

postsynaptic membraneGO:0045211

Postsynaptic transmembrane protein with a catalytically inactive acetylcholinesterase-like extracellular domain that binds neurexin LNS domains. Paralogs differ in synapse type (NLGN1 largely excitatory, NLGN2 inhibitory).

Neurexin-LRRTM bridgeProtein Complexlrrtm_bridge
Context
VertebrataNCBITaxon:7742

Annotons

LRRTM (e.g. LRRTM2): postsynaptic neurexin ligand
lrrtm_activity
Participant: Family: LRRTM family (leucine-rich repeat transmembrane neuronal proteins)
Family:
LRRTM family (leucine-rich repeat transmembrane neuronal proteins)
Representative Members: LRRTM2 (human)UniProtKB:O43300

Function

neurexin family protein bindingGO:0042043

Locations

postsynaptic membraneGO:0045211

Leucine-rich-repeat postsynaptic transmembrane protein that binds SS4-lacking neurexins and induces only excitatory synapses.

Neurexin-cerebellin-GluD tripartite bridgeProtein Complexcerebellin_gluD_bridge
Context
VertebrataNCBITaxon:7742

Annotons

Cerebellin (e.g. CBLN1): secreted neurexin-GluD adaptor
cerebellin_activity
Participant: Family: Cerebellin family
Family:
Cerebellin familyPANTHER:PTHR22923 Grounded at family level because the adaptor role is reported for cerebellin paralogs beyond CBLN1, so it is not specific to the CBLN1 subfamily (PTHR22923:SF5). The family also contains other C1q-domain proteins, so membership alone does not confer this role.
Representative Members: CBLN1 (human)UniProtKB:P23435

Function

signaling receptor regulator activityGO:0030545

Locations

synaptic cleftGO:0043083

Secreted C1q-like hexamer released from the presynaptic neuron that binds SS4-containing neurexins and the amino-terminal domain of GluD receptors, bridging the cleft.

GluD receptor (GRID1/GRID2): postsynaptic cerebellin receiver
gluD_activity
Participant: Family: Delta-family ionotropic glutamate receptors (GluD1/GluD2)
Family:
Delta-family ionotropic glutamate receptors (GluD1/GluD2)PANTHER:PTHR18966 PTHR18966 covers all ionotropic glutamate receptors; the role is restricted to the delta subfamilies PTHR18966:SF108 (GluD1) and PTHR18966:SF109 (GluD2).
Representative Members: GRID1 (human)UniProtKB:Q9ULK0 GRID2 (human)UniProtKB:O43424

Function

signaling receptor regulator activityGO:0030545

Locations

postsynaptic density membraneGO:0098839

Postsynaptic delta-family glutamate receptor whose amino-terminal domain binds cerebellin; binding is transduced through the cytoplasmic tail to organize the postsynapse rather than through channel opening.