id: MODULE:nmj_achr_clustering title: Neuromuscular junction acetylcholine receptor clustering — neural agrin, LRP4 coreceptor, MuSK kinase activation by DOK7, CRK/CRKL adaptors and rapsyn anchoring; AGRN/LRP4/MUSK/DOK7/CRK/CRKL/RAPSN description: >- At the vertebrate neuromuscular junction, nicotinic acetylcholine receptors (AChRs) are packed into the postsynaptic membrane of the skeletal muscle fiber at about 10,000 per square micrometre, directly opposite the motor nerve terminal. They get there in two ways: subsynaptic nuclei transcribe the receptor genes at a higher rate, and receptors already in the membrane are clustered by tethering to a subsynaptic scaffold. The clustering signal starts with neural agrin, the z+ splice forms of AGRN that motor neurons secrete into the synaptic basal lamina. Agrin binds LRP4, a single-pass LDL-receptor-family protein on the muscle surface. LRP4 also binds the muscle-specific receptor tyrosine kinase MuSK. The arc-shaped LRP4 ectodomain holds agrin and MuSK together in a ternary complex, and this activates MuSK. Inside the cell, the adaptor DOK7 binds the phosphorylated NPXY juxtamembrane motif of MuSK through its PTB domain. Its PH-PTB region dimerises, which drives trans-autophosphorylation of the MuSK activation loop, so DOK7 acts as an intracellular activator of the kinase. MuSK then phosphorylates two tyrosines in the DOK7 C-terminal tail, and these recruit the adaptors CRK and CRKL, which relay the signal towards the actin cytoskeleton. Rapsyn (RAPSN), a 43 kDa peripheral membrane protein on the cytoplasmic face of the postsynaptic membrane, binds the AChR and links it to the MuSK-containing scaffold. Without rapsyn, receptors do not form clusters at all. Before innervation, MuSK, LRP4, rapsyn and AChRs already form aneural clusters in the central region of the muscle (prepatterning); nerve-derived agrin then sharpens and stabilises these clusters at the synapse. Loss-of-function variants in AGRN, LRP4, MUSK, DOK7 or RAPSN cause congenital myasthenic syndromes. Autoantibodies against MuSK or LRP4 cause forms of myasthenia gravis. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000842 title: acetylcholine signaling pathway via nicotinic acetylcholine receptor statement: >- This module covers one part of the PW:0000842 diagram: the separate cluster in which Agrn is associated with Lrp4, Lrp4 and Dok7 are each associated with Musk, Rapsn is associated with the NMJ nAChR node, and Musk positively affects NMJ nAChR. It also covers the record text that describes this cluster as the prepatterning and stabilisation machinery that localises NMJ receptors (agrin binding Lrp4, Lrp4 interacting with MuSK, MuSK activation requiring Dok7, and clustering requiring rapsyn). The rest of the PW:0000842 diagram (ACh synthesis, vesicular loading, nicotinic reception and AChE clearance) is modelled in acetylcholine_signaling, which also cites PW:0000842. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000842.yaml). - source_id: GO:0071340 title: skeletal muscle acetylcholine-gated channel clustering statement: >- The GO process this module realises. It is_a receptor clustering (GO:0043113) and is part_of neuromuscular junction development (GO:0007528) and postsynaptic membrane organization (GO:0001941). In GOA it is carried by Agrn, Lrp4, Musk, Rapsn, Fnta and Dnaja3 (and their orthologues), and by none of the AChR subunits. - source_id: PMID:7675108 title: Failure of postsynaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice. statement: >- Separates the two routes to postsynaptic AChR accumulation. This module models the clustering route; synapse-specific transcription of the subunit genes is outside it. supporting_text: At least two distinct processes contribute to this accumulation. One is local synthesis - source_id: PMID:10320756 title: Distinct phenotypes of mutant mice lacking agrin, MuSK, or rapsyn. statement: >- Agrin, MuSK and rapsyn act in one pathway from the nerve signal to the receptor scaffold, and rapsyn is the component that is essential for cluster formation itself. supporting_text: Thus, although both MuSK and rapsyn are required for AChR clustering in vivo, only rapsyn is essential for cluster formation per se. notes: >- Derivation. This module was split out of modules/acetylcholine_signaling.yaml, whose boundary decision (4) excludes the agrin-LRP4-MuSK-DOK7-rapsyn set. The reason is that those proteins build the synapse rather than receiving or transducing the ACh signal. That module names GO:0071340 and the mouse GO-CAM gomodel:64c3044100000089 as the grounding for a separate module. The members come from the RGD Pathway Ontology diagram PW:0000842, which draws Agrn/Lrp4/Musk/Dok7/Rapsn as a cluster acting on the NMJ nAChR. PW:0000842 is listed as an evidence source of this module as well, because this module is derived from that cluster of the diagram. PW:0000841 (the ACh overview) and PW:0000843 (muscarinic) are not cited, because they do not draw this machinery. Boundary decisions. (1) The muscle AChR is the cargo of this process, not a participant in it, and is therefore not a part. The CLAUDE.md test is whether a product does any of the work of the process. Rapsyn does: it binds the receptor and tethers it to the scaffold, and without it no clusters form (PMID:7675108, PMID:10320756). The AChR pentamer is the thing that is gathered. Comparator check (QuickGO, GO:0071340 with is_a/part_of descendants, human/mouse/rat, October 2026): the term and its regulation children are carried by Agrn, Lrp4, Musk, Rapsn, Fnta, Dnaja3, Colq, Dvl1, Etv5 and Rer1 (several as acts_upstream_of_or_within), and by none of Chrna1, Chrnb1, Chrnd, Chrne or Chrng. Human CHRNA1 instead carries channel, signalling and NMJ-location terms (GO:0022848, GO:0095500, GO:0007274, GO:0031594), and the gene reviews used for acetylcholine_signaling record those as its core. The term's parent GO:0043113 receptor clustering is a protein-localisation process (is_a GO:0072657 protein localization to membrane), and such terms name the machinery that moves or holds the protein, not the protein that is localised. The receptor therefore appears only as the target of the rapsyn adaptor function (acetylcholine-gated channel complex GO:0005892, with CHRNA1 as the representative subunit). Its channel function is modelled in acetylcholine_signaling#nachr_muscle and is not repeated here. A module_ref part was deliberately not used, because it would make the receptor a required step of the clustering process. (2) Agrin is modelled as the neural (z+) splice class of AGRN on the canonical accession O00468. The UniProt record states that isoforms 1, 4 and 5 are the neuron-specific z+ forms that activate AChR clustering, and that the z8 insert is needed for LRP4 binding. The z- muscle and endothelial forms lack this activity. The annoton uses the AGRN gene-review core function, transmembrane receptor protein tyrosine kinase activator activity GO:0030297. This is defensible because the agrin LRP4 MuSK cryo-EM structure shows that LRP4 brings agrin into direct contact with MuSK (PMID:37252960). The mouse GO-CAM uses receptor ligand activity GO:0048018 for Agrn; that term is a sibling under signaling receptor activator activity GO:0030546, not a conflict. Agrin's laminin and dystroglycan binding, which anchor it in the basal lamina, are recorded in the AGRN review and are not modelled here. (3) LRP4 coreceptor activity GO:0015026 follows the LRP4 review core function and the GO-CAM. LRP4 also has a second role as a retrograde signal: muscle LRP4 binds the motor axon and promotes presynaptic differentiation. That role is a presynaptic-assembly process and is out of scope, like the LRP4 sclerostin/Wnt role in bone. (4) MuSK activation is one node with two annotons. MUSK carries transmembrane receptor protein tyrosine kinase activity GO:0004714 (GOA IBA plus EXP for GO:0004713). DOK7 carries protein tyrosine kinase activator activity GO:0030296, the first core function in the DOK7 review, supported by the Dok7 PH-PTB dimer structure (PMID:20603078). (5) The DOK7 C-terminal tail to CRK/CRKL relay is a required part. DOK7's second review core function is transmembrane receptor protein tyrosine kinase adaptor activity GO:0005068, and CRK and CRKL carry signaling adaptor activity GO:0035591. CRK has this by IDA; CRKL has it by IBA, and the mouse GO-CAM uses it for both Crk and Crkl. Crk and Crk-L are redundant, so they are one family annoton, and only loss of both in muscle gives severe NMJ defects (PMID:21041412). Further downstream, the GO-CAM continues through FARP1 guanyl-nucleotide exchange factor activity, protein geranylgeranyltransferase I (FNTA), RAC1 and positive regulation of Rac protein signal transduction (GO:0035022) to postsynaptic actin organisation. That Rac/actin effector arm is not modelled, because RGD does not draw it and its members (FARP1, FNTA, RAC1, and the Abl/Src-family kinases that phosphorylate the AChR beta subunit) are not on the RGD gene list. It is a candidate for a later extension. (6) Candidates considered and not added. TID1/DNAJA3 binds MuSK and is required for agrin-induced clustering in mouse myotubes. Its human and rat GOA rows for GO:0071340 are ISS/ISO only, and no paper on it was cached and read for this module, so it is recorded here only. Neuregulin/ErbB-driven synapse-specific transcription, the Wnt coreceptor roles of MuSK and LRP4, ColQ/perlecan anchoring of AChE (which sits in acetylcholine_signaling), and NMJ formation in general (GO:0007528, GO:0051124) are out of scope. ACh reception itself is acetylcholine_signaling. (7) Rapsyn's molecular function is protein-macromolecule adaptor activity GO:0030674, as in the mouse GO-CAM. The only experimental MF row in GOA is acetylcholine receptor binding GO:0033130 (mouse IDA, transferred to human by IBA), which describes the binding but not the bridging role. GO-CAM. gomodel:64c3044100000089 "Skeletal muscle acetylcholine-gated channel clustering 1 (Mouse)" contains every annoton modelled here: Agrn, Lrp4, Musk (two activities), Dok7 (two activities), Crk, Crkl and Rapsn. Its activity links are recorded under gocam_associations. Possible upstream issue: in that model the Rapsn activity (GO:0030674, part_of GO:0071340) has input Chrna9 (MGI:MGI:1202403). The evidence cited for it is PMID:18420419, an inner-ear hair-cell study of rapsyn and the alpha9 receptor. In a skeletal-muscle clustering model the expected input would be the muscle receptor (Chrna1 and partners), so the has_input may have been carried over from the hair-cell paper. PMID:18420419 is not cached and its full text was not read, so this is flagged as a question rather than asserted as an error. No human GO-CAM covers this pathway. Gene reviews exist for AGRN, LRP4 and DOK7, and their core molecular functions were used. MUSK, RAPSN, CRK and CRKL have no review yet; their functions come from GOA and the cited literature. PANTHER family ids and PTNs are deliberately not asserted. module: id: nmj_achr_clustering label: Neuromuscular junction acetylcholine receptor clustering module_type: BIOLOGICAL_PROCESS concepts: - preferred_term: skeletal muscle acetylcholine-gated channel clustering term: id: GO:0071340 label: skeletal muscle acetylcholine-gated channel clustering description: >- The process as a whole: gathering of muscle AChRs into a dense postsynaptic patch opposite the nerve terminal. Part of neuromuscular junction development (GO:0007528), which is broader and is not asserted. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens cell_types: - preferred_term: skeletal muscle fiber term: id: CL:0008002 label: skeletal muscle fiber cellular_components: - preferred_term: neuromuscular junction term: id: GO:0031594 label: neuromuscular junction parts: - order: 1 role: nerve-derived clustering signal node: id: agrin_signal label: Neural (z+) agrin from the motor nerve terminal module_type: SIGNALING_PATHWAY description: >- Motor neurons secrete z+ agrin, which is held in the synaptic basal lamina and engages LRP4 on the muscle surface. Agrin also contacts MuSK directly once both are bound to LRP4. annotons: - id: agrn_musk_activator label: Neural agrin activates MuSK through LRP4 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AGRN (neural z+ isoforms) term: id: UniProtKB:O00468 label: Agrin function: preferred_term: transmembrane receptor protein tyrosine kinase activator activity term: id: GO:0030297 label: transmembrane receptor protein tyrosine kinase activator activity targets: - preferred_term: MUSK term: id: UniProtKB:O15146 label: Muscle, skeletal receptor tyrosine-protein kinase processes: - preferred_term: cell surface receptor protein tyrosine kinase signaling pathway term: id: GO:0007169 label: cell surface receptor protein tyrosine kinase signaling pathway locations: - preferred_term: basement membrane term: id: GO:0005604 label: basement membrane role_description: >- The instructive nerve signal. Only the neuron-specific z+ splice forms carry clustering activity; this matches the AGRN gene-review core function. evidence: - source_id: file:human/AGRN/AGRN-uniprot.txt statement: Only the neural z+ agrin isoforms are potent AChR-clustering activators. supporting_text: 'Isoform 1, isoform 4 and isoform 5: neuron-specific (z+) isoforms that contain C-terminal insertions of 8-19 AA are potent activators of AChR clustering.' - source_id: PMID:8653787 statement: Agrin signals through a MuSK-containing receptor complex with a myotube-specific accessory component (later identified as LRP4). supporting_text: Here we demonstrate that agrin acts via a receptor complex that includes MuSK as well as a myotube-specific accessory component. - source_id: PMID:37252960 statement: In the ternary complex LRP4 brings agrin into direct contact with MuSK. supporting_text: This structure reveals that arc-shaped LRP4 simultaneously recruits both agrin and MuSK to its central cavity, thereby promoting a direct interaction between agrin and MuSK. gocam_associations: - model: gomodel:64c3044100000089 activity: gomodel:64c3044100000089/64c3044100000098 title: Skeletal muscle acetylcholine-gated channel clustering 1 (Mouse) description: >- Agrn receptor ligand activity (GO:0048018) in extracellular region, directly positively regulating Lrp4 coreceptor activity. - order: 2 role: agrin coreceptor node: id: lrp4_coreceptor label: LRP4 binds agrin and MuSK module_type: SIGNALING_PATHWAY description: >- Muscle LRP4 binds neural agrin and MuSK and assembles the extracellular agrin/LRP4/MuSK signalling complex. annotons: - id: lrp4_agrin_coreceptor label: LRP4 coreceptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LRP4 term: id: UniProtKB:O75096 label: Low-density lipoprotein receptor-related protein 4 function: preferred_term: coreceptor activity term: id: GO:0015026 label: coreceptor activity processes: - preferred_term: cell surface receptor protein tyrosine kinase signaling pathway term: id: GO:0007169 label: cell surface receptor protein tyrosine kinase signaling pathway locations: - preferred_term: postsynaptic membrane term: id: GO:0045211 label: postsynaptic membrane role_description: >- The agrin receptor of muscle; it is needed for agrin binding, MuSK activation and AChR clustering. This matches the LRP4 gene-review core function. evidence: - source_id: PMID:18848351 statement: Lrp4 is the agrin receptor and forms a complex with MuSK. supporting_text: Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin. - source_id: PMID:18957220 statement: LRP4 knockdown reduces agrin binding, MuSK phosphorylation and AChR clustering. supporting_text: Suppression of LRP4 expression in muscle cells attenuates agrin binding, agrin-induced MuSK tyrosine phosphorylation, and AChR clustering. - source_id: PMID:18957220 statement: The LRP4-MuSK complex is stimulated by agrin. supporting_text: LRP4 also forms a complex with MuSK in a manner that is stimulated by agrin. gocam_associations: - model: gomodel:64c3044100000089 activity: gomodel:64c3044100000089/64c3044100000674 title: Skeletal muscle acetylcholine-gated channel clustering 1 (Mouse) description: Lrp4 coreceptor activity (GO:0015026), directly positively regulating Musk. - order: 3 role: MuSK kinase activation node: id: musk_activation label: MuSK activation, with DOK7 as cytoplasmic activator module_type: SIGNALING_PATHWAY description: >- Agrin-bound LRP4 activates MuSK. DOK7 binds the phosphorylated MuSK juxtamembrane NPXY motif, dimerises through its PH-PTB region and promotes trans-autophosphorylation of the MuSK activation loop. Overexpressed DOK7 can activate MuSK without agrin, which is thought to underlie aneural prepatterning. annotons: - id: musk_rtk label: MuSK receptor tyrosine kinase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MUSK term: id: UniProtKB:O15146 label: Muscle, skeletal receptor tyrosine-protein kinase function: preferred_term: transmembrane receptor protein tyrosine kinase activity term: id: GO:0004714 label: transmembrane receptor protein tyrosine kinase activity targets: - preferred_term: DOK7 term: id: UniProtKB:Q18PE1 label: Protein Dok-7 processes: - preferred_term: cell surface receptor protein tyrosine kinase signaling pathway term: id: GO:0007169 label: cell surface receptor protein tyrosine kinase signaling pathway locations: - preferred_term: postsynaptic membrane term: id: GO:0045211 label: postsynaptic membrane role_description: >- The signalling kinase of the pathway; it autophosphorylates and also phosphorylates the DOK7 C-terminal tail. evidence: - source_id: PMID:8653787 statement: MuSK is the receptor tyrosine kinase of the motor endplate through which agrin acts. supporting_text: MuSK is a receptor tyrosine kinase localized to the motor endplate, seemingly well positioned to receive a key nerve-derived signal. - source_id: PMID:21041412 statement: Agrin-activated MuSK phosphorylates the DOK7 C-terminal tail. supporting_text: We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7 gocam_associations: - model: gomodel:64c3044100000089 activity: gomodel:64c3044100000089/64c3044100000096 title: Skeletal muscle acetylcholine-gated channel clustering 1 (Mouse) description: >- Musk protein tyrosine kinase activity (GO:0004713) in postsynaptic membrane, directly positively regulating Dok7 and Fnta. - model: gomodel:64c3044100000089 activity: gomodel:64c3044100000089/64d5781900001202 title: Skeletal muscle acetylcholine-gated channel clustering 1 (Mouse) description: >- Second Musk kinase activity with Dok7 as input, directly positively regulating the Dok7 activity that recruits Crk/Crkl. - id: dok7_musk_activator label: DOK7 activates MuSK from the cytoplasm participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DOK7 term: id: UniProtKB:Q18PE1 label: Protein Dok-7 function: preferred_term: protein tyrosine kinase activator activity term: id: GO:0030296 label: protein tyrosine kinase activator activity targets: - preferred_term: MUSK term: id: UniProtKB:O15146 label: Muscle, skeletal receptor tyrosine-protein kinase processes: - preferred_term: cell surface receptor protein tyrosine kinase signaling pathway term: id: GO:0007169 label: cell surface receptor protein tyrosine kinase signaling pathway locations: - preferred_term: postsynaptic membrane term: id: GO:0045211 label: postsynaptic membrane role_description: >- Needed for MuSK activation, AChR clustering and synapse formation. This matches the first core function in the DOK7 gene review. evidence: - source_id: PMID:20603078 statement: DOK7 is both a MuSK substrate and an activator of the MuSK kinase. supporting_text: Unique among adaptor proteins recruited to RTKs, Dok7 is not only a substrate of MuSK, but also an activator of MuSK - source_id: PMID:20603078 statement: The Dok7 PH-PTB dimer drives MuSK trans-autophosphorylation. supporting_text: The structure and biochemical data reveal a dimeric arrangement of Dok7 PH-PTB that facilitates trans-autophosphorylation of the kinase activation loop. - source_id: PMID:16794080 statement: Dok-7-null mice form no AChR clusters. supporting_text: Mice lacking Dok-7 formed neither acetylcholine receptor clusters nor neuromuscular synapses. gocam_associations: - model: gomodel:64c3044100000089 activity: gomodel:64c3044100000089/64c3044100000694 title: Skeletal muscle acetylcholine-gated channel clustering 1 (Mouse) description: >- Dok7 signaling adaptor activity (GO:0035591) with Musk as input, directly positively regulating Musk. - order: 4 role: DOK7-CRK/CRKL downstream relay node: id: dok7_crk_relay label: Phospho-DOK7 recruits CRK and CRKL module_type: SIGNALING_PATHWAY description: >- MuSK phosphorylates two tyrosines in the DOK7 C-terminal tail. These recruit the SH2-SH3 adaptors CRK and CRKL, which relay the signal towards the postsynaptic actin cytoskeleton. annotons: - id: dok7_tail_adaptor label: DOK7 C-terminal tail adaptor for CRK/CRKL participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DOK7 term: id: UniProtKB:Q18PE1 label: Protein Dok-7 function: preferred_term: transmembrane receptor protein tyrosine kinase adaptor activity term: id: GO:0005068 label: transmembrane receptor protein tyrosine kinase adaptor activity processes: - preferred_term: cell surface receptor protein tyrosine kinase signaling pathway term: id: GO:0007169 label: cell surface receptor protein tyrosine kinase signaling pathway locations: - preferred_term: postsynaptic membrane term: id: GO:0045211 label: postsynaptic membrane role_description: >- The second DOK7 core function in its gene review; most congenital myasthenia mutations in DOK7 truncate this C-terminal region. evidence: - source_id: PMID:21041412 statement: Phosphorylated DOK7 tail tyrosines recruit Crk and Crk-L. supporting_text: "which leads to recruitment of two adapter proteins: Crk and Crk-L" gocam_associations: - model: gomodel:64c3044100000089 activity: gomodel:64c3044100000089/64d5781900001209 title: Skeletal muscle acetylcholine-gated channel clustering 1 (Mouse) description: Dok7 signaling adaptor activity, directly positively regulating Crk and Crkl. - id: crk_crkl_adaptor label: CRK/CRKL signaling adaptors participant: selector_type: FAMILY family: preferred_term: CRK-family SH2-SH3 adaptors (CRK, CRKL) representative_members: - preferred_term: CRK term: id: UniProtKB:P46108 label: Adapter molecule crk - preferred_term: CRKL term: id: UniProtKB:P46109 label: Crk-like protein function: preferred_term: signaling adaptor activity term: id: GO:0035591 label: signaling adaptor activity processes: - preferred_term: cell surface receptor protein tyrosine kinase signaling pathway term: id: GO:0007169 label: cell surface receptor protein tyrosine kinase signaling pathway role_description: >- CRK and CRKL are redundant here; loss of both in muscle is needed to produce severe NMJ defects. evidence: - source_id: PMID:21041412 statement: Muscle-specific loss of both Crk and Crk-L severely disrupts neuromuscular synapses. supporting_text: selective inactivation of Crk and Crk-L in skeletal muscle leads to severe defects in neuromuscular synapses in vivo gocam_associations: - model: gomodel:64c3044100000089 activity: gomodel:64c3044100000089/64d5781900001211 title: Skeletal muscle acetylcholine-gated channel clustering 1 (Mouse) description: Crk signaling adaptor activity, directly positively regulating Farp1. - model: gomodel:64c3044100000089 activity: gomodel:64c3044100000089/64d5781900001218 title: Skeletal muscle acetylcholine-gated channel clustering 1 (Mouse) description: Crkl signaling adaptor activity. - order: 5 role: AChR anchoring and cluster formation node: id: rapsyn_anchoring label: Rapsyn tethers AChRs to the MuSK-containing scaffold module_type: BIOLOGICAL_PROCESS description: >- Rapsyn, on the cytoplasmic face of the postsynaptic membrane, binds the AChR and links it to the subsynaptic scaffold organised around MuSK, gathering receptors into high-density clusters. The receptor is the cargo of this step. annotons: - id: rapsn_achr_adaptor label: Rapsyn AChR-scaffold adaptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RAPSN term: id: UniProtKB:Q13702 label: 43 kDa receptor-associated protein of the synapse function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity targets: - preferred_term: muscle nicotinic acetylcholine receptor term: id: GO:0005892 label: acetylcholine-gated channel complex - preferred_term: CHRNA1 (representative muscle AChR subunit) term: id: UniProtKB:P02708 label: Acetylcholine receptor subunit alpha processes: - preferred_term: skeletal muscle acetylcholine-gated channel clustering term: id: GO:0071340 label: skeletal muscle acetylcholine-gated channel clustering locations: - preferred_term: postsynaptic specialization membrane term: id: GO:0099634 label: postsynaptic specialization membrane role_description: >- The receptor-anchoring component. Of the pathway members, rapsyn is the one essential for cluster formation itself. evidence: - source_id: PMID:7675108 statement: Rapsyn is the key component of the subsynaptic complex that AChRs tether to. supporting_text: they form high-density clusters by tethering to a subsynaptic cytoskeletal complex. A key component of this complex is rapsyn - source_id: PMID:7675108 statement: Rapsyn-null mice form no AChR clusters. supporting_text: We report that rapsyn is essential for the formation of AChR clusters - source_id: PMID:9136771 statement: MuSK forms the primary scaffold to which rapsyn attaches AChRs and other synaptic components. supporting_text: suggesting that MuSK forms a primary structural scaffold to which rapsyn attaches other synaptic components gocam_associations: - model: gomodel:64c3044100000089 activity: gomodel:64c3044100000089/64c3044100000676 title: Skeletal muscle acetylcholine-gated channel clustering 1 (Mouse) description: >- Rapsn protein-macromolecule adaptor activity (GO:0030674) part_of GO:0071340; its has_input is Chrna9 rather than a muscle subunit (see notes). connections: - source: agrin_signal target: lrp4_coreceptor connection_type: POSITIVELY_REGULATES description: Neural agrin binds and engages LRP4. - source: lrp4_coreceptor target: musk_activation connection_type: POSITIVELY_REGULATES description: The agrin-LRP4 complex activates MuSK. - source: musk_activation target: dok7_crk_relay connection_type: POSITIVELY_REGULATES description: Active MuSK phosphorylates the DOK7 tail, which recruits CRK/CRKL. - source: musk_activation target: rapsyn_anchoring connection_type: POSITIVELY_REGULATES description: >- MuSK signalling organises the scaffold to which rapsyn tethers AChRs (RGD's "Musk positively affects NMJ nAChR" edge, read as receptor localisation).