FERM and PDZ domain-containing protein 2 (Frmpd2) is a multi-domain scaffold protein that organizes signaling complexes at the cell membrane. It contains an N-terminal KIND domain, a FERM domain that binds phosphatidylinositols for membrane anchoring, and three PDZ domains that mediate protein-protein interactions. In the mouse nervous system, Frmpd2 functions as a postsynaptic scaffold that anchors NMDA receptor subunits (GluN2A/GluN2B) at synapses via its PDZ2 domain, and participates in cone photoreceptor synapse formation through PDZ3-mediated interaction with LRIT1. Based on studies of the human ortholog, Frmpd2 also contributes to epithelial cell polarity by localizing to the basolateral membrane and regulating tight junction formation, and serves as a scaffold for the NOD2 innate immune signalosome in intestinal epithelial cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasmic localization is consistent with Frmpd2 being a peripheral membrane protein that is recruited to membranes via its FERM domain. The protein is not an integral membrane protein and would be cytoplasmic when not membrane-associated. Reason: Consistent with known biology of peripheral membrane scaffold proteins Supporting Evidence: PMID:19706687 FRMPD2 is localized in a polarized fashion in epithelial cells at the basolateral membrane UniProt:A0A140LI67 SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane localization is well supported. The FERM domain binds phosphatidylinositols for membrane anchoring, and Frmpd2 localizes to postsynaptic membranes in neurons and basolateral membranes in epithelia. Reason: Well supported by multiple studies showing membrane localization Supporting Evidence: PMID:31196628 the Frmpd2 is specifically expressed at postsynaptic membrane PMID:19706687 the FERM domain of FRMPD2 binds phosphatidylinositols and is sufficient for membrane localization |
| GO:0045177 apical part of cell | IBA GO_REF:0000033 | REMOVE | Summary: This annotation is questionable for Frmpd2. The literature consistently shows that FRMPD2 localizes to the BASOLATERAL membrane, not the apical surface. The PDZ2 domain and FERM domain together restrict FRMPD2 to the basolateral compartment. The IBA does not come from a FRMPD paralog - the node behind it (PANTHER:PTN007679700) belongs to PTHR19964, PANTHER family name "MULTIPLE PDZ DOMAIN PROTEIN", and is seeded by MPDZ and PATJ, multi-PDZ apical tight-junction / Crumbs-complex scaffolds, whereas UniProt classifies Frmpd2 in PTHR46900:SF4. Reason: Contradicts direct experimental evidence showing basolateral, not apical, localization. Apical part of cell and basolateral plasma membrane (GO:0016323, accepted below as the primary location) are the mutually exclusive halves of a polarized epithelial cell, and PMID:19706687 shows Frmpd2 is actively restricted to the basolateral side, so this is a mutually-exclusive compartment error rather than a broad subsuming parent. Removing it is consistent with retaining GO:0005923 bicellular tight junction as non-core: in GO, bicellular tight junction is not part_of apical part of cell - its is_a/part_of ancestors run through apical junction complex (GO:0043296) and cell-cell junction (GO:0005911), not GO:0045177 - so a junctional pool at the apical end of the lateral membrane does not entail residence in the apical domain. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN007679700 SUPPORTS SOURCE BUT NOT TARGET This node belongs to PTHR19964, PANTHER family name "MULTIPLE PDZ DOMAIN PROTEIN", not to the family UniProt assigns to the target (PTHR46900:SF4 "FERM AND PDZ DOMAIN CONTAINING 2"; the PTHR46900 family name is "TYROSINE-PROTEIN PHOSPHATASE NON-RECEPTOR TYPE 13"). Human FRMPD2 (Q68DX3) does appear among this node's seeds for GO:0005886, so the cross-family reach is a node placement PANTHER itself made rather than a data error. Per the project framework cross-family propagation is triage evidence, not a verdict - the verdict here rests on the target-specific evidence for active basolateral restriction. MGI:MGI:1277960 · mouse Patj (PATJ, crumbs cell polarity complex component) SUPPORTS SOURCE BUT NOT TARGET A Crumbs-complex multi-PDZ scaffold whose apical residence is well established; the term is correct for it. Its apical localization is a property of the Crumbs/PATJ apical polarity module, which Frmpd2 is not part of. MGI:MGI:1343489 · mouse Mpdz (multiple PDZ domain crumbs cell polarity complex component) SUPPORTS SOURCE BUT NOT TARGET Second multi-PDZ apical tight-junction scaffold seed; correct at the source, not transferable to a basolaterally restricted protein. UniProtKB:E2QYC9 · dog PATJ (InaD-like protein) SUPPORTS SOURCE BUT NOT TARGET Non-mammalian-model ortholog of the PATJ seed; adds depth to the PATJ clade, not to the target's subfamily. UniProtKB:Q8NI35 · human PATJ (InaD-like protein) SUPPORTS SOURCE BUT NOT TARGET IBD seed present in the local PAINT cache for this node; same PATJ apical-polarity biology as the mouse and dog seeds. RGD:3105 · rat Mpdz SUPPORTS SOURCE BUT NOT TARGET IBD seed present in the local PAINT cache for this node but not listed in the GOA WITH/FROM; same MPDZ apical-scaffold biology. Supporting Evidence: PMID:19706687 the FERM domain and binding of the PDZ2 domain to the armadillo protein p0071 are required for basolateral restriction of FRMPD2 |
| GO:0005923 bicellular tight junction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Frmpd2 partially colocalizes with the tight junction marker ZO-1 (TJP1) in epithelial cells, and its knockdown impairs tight junction formation. However, Frmpd2 is primarily a basolateral membrane protein that is recruited to cell-cell contacts in an E-cadherin-dependent manner. The tight junction colocalization is partial rather than exclusive. Reason: Partial colocalization with tight junctions is secondary to the primary basolateral membrane localization; evidence is from human ortholog. Keeping this term while removing GO:0045177 apical part of cell above is not inconsistent: in GO, bicellular tight junction is not part_of apical part of cell, and the supporting evidence here is target-specific (partial ZO-1 colocalization and impaired tight-junction formation on knockdown) rather than a claim of apical-domain residence. Supporting Evidence: PMID:19706687 FRMPD2 is localized in a polarized fashion in epithelial cells at the basolateral membrane and partially colocalizes with the tight-junction marker protein Zonula-occludens-1 |
| GO:0005545 1-phosphatidylinositol binding | IBA GO_REF:0000033 | MODIFY | Summary: The FERM domain of FRMPD2 binds phosphatidylinositols, specifically PtdIns(3,4)P2 according to UniProt. This binding is essential for membrane localization. The term 1-phosphatidylinositol binding (GO:0005545) is a reasonable annotation, though the more specific phosphatidylinositol binding (GO:0035091) or phosphatidylinositol-3,4-bisphosphate binding would be more precise if such a term exists. Reason: The FERM domain specifically binds PtdIns(3,4)P2 according to UniProt; the more specific phosphatidylinositol-3,4-bisphosphate binding term better captures the demonstrated lipid specificity Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN000462700 SUPPORTS TRANSFER Unlike the GO:0045177 row above, this node is in PTHR46900 - the target's own PANTHER family, to whose subfamily SF4 UniProt assigns both mouse Frmpd2 and human FRMPD2 - so the lipid-binding transfer is within the FRMPD2 orthology group and the node placement is not at issue. UniProtKB:Q68DX3 · human FRMPD2 (FERM and PDZ domain-containing protein 2) SUPPORTS TRANSFER The 1:1 human ortholog and the sole IBD seed, which is not a weakness: the FERM-domain phosphoinositide binding it establishes is exactly the property inherited by the target. The fault is only in which lipid the GO term names. GO:0043325 is not a child of GO:0005545 - the two are different phosphoinositide species, GO:0005545 being binding to unphosphorylated PtdIns - so this is a wrong-ligand re-scope rather than a parent-to-child narrowing, and no granularity failure mode is asserted. Proposed replacements: phosphatidylinositol-3,4-bisphosphate binding Supporting Evidence: PMID:19706687 the FERM domain of FRMPD2 binds phosphatidylinositols and is sufficient for membrane localization UniProt:A0A140LI67 Binds phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) (By similarity) |
| GO:0016323 basolateral plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Basolateral plasma membrane localization is the primary site of FRMPD2 in polarized epithelial cells. This is mediated by the FERM domain binding phosphatidylinositols and the PDZ2 domain binding p0071/PKP4. In neurons, the protein localizes to postsynaptic density which is functionally analogous. Reason: Strongly supported primary localization in epithelial cells, directly demonstrated in human ortholog Supporting Evidence: PMID:19706687 FRMPD2 is localized in a polarized fashion in epithelial cells at the basolateral membrane |
| GO:0070830 bicellular tight junction assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Knockdown of FRMPD2 in Caco-2 cells impairs tight junction formation, supporting a role in tight junction assembly. This is consistent with its scaffold function at cell-cell junctions and partial colocalization with ZO-1. Reason: Supporting evidence from human ortholog knockdown; secondary to core scaffold function Supporting Evidence: PMID:19706687 Downregulation of FRMPD2 protein in Caco-2 cells is associated with an impairment of tight junction formation |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Duplicate of the IBA annotation above. IEA annotation from UniProt subcellular location mapping. Consistent with Frmpd2 being a peripheral membrane protein. Reason: Redundant with IBA annotation; consistent with known localization |
| GO:0005923 bicellular tight junction | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA transfer from human ortholog Q68DX3. Consistent with partial colocalization with ZO-1 at tight junctions. Reason: Consistent with partial tight junction colocalization; not the primary localization |
| GO:0014069 postsynaptic density | IEA GO_REF:0000044 | ACCEPT | Summary: Postsynaptic density localization is directly demonstrated for mouse Frmpd2, where it scaffolds NMDA receptors. Lu et al. showed Frmpd2 is specifically expressed at the postsynaptic membrane and directly binds GluN2A/GluN2B. Reason: Directly demonstrated in mouse by Lu et al. 2019; this is a core localization for the synaptic scaffold function Supporting Evidence: PMID:31196628 the Frmpd2 is specifically expressed at postsynaptic membrane |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: IEA transfer from human ortholog. Redundant with IBA annotation. Well supported by human studies. Reason: Redundant with IBA annotation; well supported |
| GO:0005545 1-phosphatidylinositol binding | IEA GO_REF:0000107 | MODIFY | Summary: IEA from Ensembl Compara ortholog transfer. Same assessment as IBA annotation above - should be modified to more general phosphatidylinositol binding. Reason: Same as IBA annotation - more specific PtdIns(3,4)P2 binding term better captures the demonstrated lipid specificity Proposed replacements: phosphatidylinositol-3,4-bisphosphate binding |
| GO:0070830 bicellular tight junction assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from Ensembl Compara. Redundant with IBA annotation. Supported by knockdown evidence in human Caco-2 cells. Reason: Redundant with IBA; secondary function based on human ortholog studies |
| GO:0005545 1-phosphatidylinositol binding | ISO GO_REF:0000119 | MODIFY | Summary: ISO transfer from human ortholog Q68DX3. Same assessment as other PI binding annotations - should use more general term. Reason: Same as other PI binding annotations - more specific PtdIns(3,4)P2 binding term is more accurate Proposed replacements: phosphatidylinositol-3,4-bisphosphate binding |
| GO:0005923 bicellular tight junction | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO transfer from human ortholog Q68DX3. Consistent with partial ZO-1 colocalization. Reason: Secondary localization based on human ortholog |
| GO:0016323 basolateral plasma membrane | ISO GO_REF:0000119 | ACCEPT | Summary: ISO transfer from human ortholog Q68DX3. Well supported primary localization in epithelial cells. Reason: Consistent and well-supported localization |
| GO:0035591 signaling adaptor activity | IDA PMID:31196628 The second PDZ domain of scaffold protein Frmpd2 binds to Gl... | NEW | Summary: Frmpd2 functions as a signaling adaptor/scaffold that bridges NMDA receptor subunits to the postsynaptic density. Its multi-PDZ domain architecture and FERM domain membrane anchoring are hallmarks of signaling adaptor activity. Also supported by scaffolding of NOD2 signalosome (human ortholog). Reason: Core molecular function not captured by existing annotations; directly supported by multiple studies Supporting Evidence: PMID:31196628 the scaffold protein Frmpd2 is probably involved in synaptic NMDA receptors-mediated neural excitatory and neurotoxicity in a PDZ2 domain-dependent manner PMID:19706687 FRMPD2 is a potential scaffolding protein consisting of an N-terminal KIND domain, a FERM domain and three PDZ domains file:mouse/Frmpd2/Frmpd2-deep-research-falcon.md Comprehensive literature review confirms Frmpd2 functions as a multi-context scaffold protein with roles in NMDAR anchoring, photoreceptor synapse organization, epithelial polarity, and NOD2 innate immune signaling |
| GO:0035254 glutamate receptor binding | IDA PMID:31196628 The second PDZ domain of scaffold protein Frmpd2 binds to Gl... | NEW | Summary: The PDZ2 domain of Frmpd2 directly binds GluN2A and GluN2B C-termini as demonstrated by co-immunoprecipitation, GST pull-down, and surface plasmon resonance. Crystal structure of the interaction solved. Reason: Direct experimental evidence for glutamate receptor binding in mouse Supporting Evidence: PMID:31196628 the second PDZ (PDZ2) domain but not the first or third PDZ domain of Frmpd2 binds to the C-terminus of GluN2A and GluN2B |
| GO:0097114 NMDA glutamate receptor clustering | IDA PMID:31196628 The second PDZ domain of scaffold protein Frmpd2 binds to Gl... | NEW | Summary: Frmpd2 anchors NMDA receptor subunits at synapses via direct PDZ2-mediated binding. This scaffolding function promotes NMDAR clustering at the postsynaptic density. Reason: Directly supported by binding and localization data in mouse Supporting Evidence: PMID:31196628 Frmpd2 was reported to interact with postsynaptic excitatory N-methyl-d-aspartic acid (NMDA) receptors in vivo and in vitro |
| GO:0098684 photoreceptor ribbon synapse | IDA PMID:29590622 Lrit1, a Retinal Transmembrane Protein, Regulates Selective ... | NEW | Summary: Frmpd2 localizes to photoreceptor synapses where it interacts with LRIT1 and participates in the Frmpd2-Lrit1-mGluR6 synaptic complex. Reason: Direct evidence from mouse retina showing Frmpd2 at photoreceptor synapses Supporting Evidence: PMID:29590622 Lrit1 interacts with Frmpd2, a photoreceptor scaffold protein |
| GO:0051963 regulation of synapse assembly | IDA PMID:29590622 Lrit1, a Retinal Transmembrane Protein, Regulates Selective ... | NEW | Summary: Frmpd2 participates in the Frmpd2-Lrit1-mGluR6 axis that regulates selective synapse formation between cone photoreceptors and cone ON-bipolar cells. Reason: Supported by Lrit1 interaction data and role in cone synapse formation Supporting Evidence: PMID:29590622 the Frmpd2-Lrit1-mGluR6 axis regulates selective synapse formation in cone photoreceptors and is essential for normal visual function |
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Download this section (compressed HTML)Q: Does Frmpd2 play a role in NOD2-mediated innate immune signaling in mouse intestinal epithelial cells, or is this function specific to human FRMPD2?
Suggested experts: Lipinski S, Rosenstiel P
Q: What is the functional significance of the KIND domain in Frmpd2? It is present in the protein but its specific role has not been characterized.
Q: Does Frmpd2 interact with actin filaments via its FERM domain in vivo, and does this contribute to excitatory synapse morphogenesis as suggested by the bioRxiv preprint?
Suggested experts: Lu X
Experiment: Generate Frmpd2 conditional knockout mice (neuron-specific) and assess NMDAR-mediated synaptic transmission via electrophysiology in hippocampal slices. Monitor for spontaneous seizures and test in epilepsy paradigms.
Hypothesis: Frmpd2 knockout in mouse would impair NMDAR-mediated synaptic transmission and may cause epilepsy-related phenotypes.
Type: knockout/electrophysiology
Experiment: Generate Frmpd2 retina-specific knockout mice and assess cone photoreceptor pedicle morphology and cone ON-bipolar cell responses by ERG and immunohistochemistry.
Hypothesis: Frmpd2 is required for cone photoreceptor synapse formation independently of Lrit1.
Type: knockout/electrophysiology
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