LRCH3 is a cytosolic leucine-rich-repeat and calponin-homology-domain protein that organizes a DOCK7-induced septin displacement module in cultured human cells. Its leucine-rich repeats associate with the DHR-2 region of the RAC1/CDC42 guanine-nucleotide exchange factor DOCK7, while an intervening LRCH3 region binds directly to the cargo-binding tail of the actin motor MYO6, allowing LRCH3 to link the two proteins. The LRCH3 calponin-homology region recruits and oligomerizes SEPT7 in a relocalization assay, and LRCH3 expression displaces septins from actin filaments and promotes cytosolic septin-ring structures, especially with the DOCK7 DHR-2 region. Co-immunoprecipitation, interaction mapping, and two-hybrid evidence support a MYO6-LRCH3-DOCK7 trimeric DISP complex in the tested cell systems; endogenous stoichiometry and tissue generality remain unresolved. Septins were not recovered in LRCH3 immunoprecipitates, so their relationship to DISP is functional relocation rather than established complex membership, and direct LRCH3-actin binding has not been demonstrated. Expressed LRCH3 also accumulates at the cleavage furrow from anaphase in HeLa cells. Four splice isoforms are described, without evidence for endogenous functional specialization.
Definition: A protein-containing complex, also known as the DISP complex, composed of MYO6, LRCH3, and DOCK7 that links the MYO6 cargo-binding tail to the DOCK7 DHR-2 region through distinct binding sites on LRCH3 and participates in remodeling the septin cytoskeleton.
Justification: The named DOCK7-induced septin displacement (DISP) complex has mapped trimeric topology supported by proximity labeling, co-immunoprecipitation, domain mapping, and direct LRCH3-MYO6 two-hybrid evidence, but GO has no specific cellular- component term for it. A specific term would distinguish the MYO6-LRCH3-DOCK7 complex from generic protein-containing complexes and from septins, which were not recovered in LRCH3 immunoprecipitates and are not proposed as subunits.
Parent term: protein-containing complex
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: LRCH3 has a cytosolic pool consistent with its role in the MYO6-DOCK7-septin module. Reason: The phylogenetic cytosol annotation agrees with HPA immunofluorescence and with direct cytoplasmic localization and septin-remodeling evidence from PMID:29467281. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002699691 SUPPORTS TRANSFER The LRCH3 family node supports conserved cytosolic localization. UniProtKB:Q96II8 SUPPORTS TRANSFER Self-reference: the target is its own IBD seed, which is expected rather than circular -- its own IDA annotation to this term is one of the descendant evidences behind the IBD. The IBA then asserts the additional claim that the function is inherited rather than lineage-specific. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping places LRCH3 in the cytoplasm. Reason: This conservative mapping agrees with the direct cytoplasm annotation and the cytosolic localization observed by immunofluorescence. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER Exact UniProt vocabulary source for cytoplasmic localization. |
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | MARK AS OVER ANNOTATED | Summary: A mammalian interaction screen reported an LRCH3-DOCK7 contact at filamentous actin. Reason: This screen-level IPI is compatible with the focused LRCH3-DOCK7 evidence in PMID:29467281, but the abstract-only source does not define LRCH3 activity and generic protein binding is uninformative. The live occurs_in extension is retained as provenance rather than treated as proof of direct actin binding. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: A proteome-scale binary-interaction map reported an LRCH3 contact with DOCK8 isoform 2. Reason: The screen preserves a tested physical contact but supplies no LRCH3-specific regulatory mechanism, and GO:0005515 is not an informative activity term. A DOCK8 interaction does not justify transferring the DOCK8-inhibitory function of LRCH1 or the peripheral-recruitment observations for LRCH2. |
| GO:0005515 protein binding | IPI PMID:29467281 The MYO6 interactome reveals adaptor complexes coordinating ... | MODIFY | Summary: LRCH3 binds distinct regions of MYO6 and DOCK7 and links the two proteins in the DISP module. Reason: PMID:29467281 maps MYO6 and DOCK7 to distinct sites on LRCH3 and explicitly concludes that LRCH3 is their linker. GO:0030674 protein-macromolecule adaptor activity captures this demonstrated bridging role more informatively than generic protein binding. The merged entities preserve DOCK7 and both tested MYO6 product identifiers; the live filamentous-actin extension belongs to the DOCK7 assertion within the normalized union. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:29467281 The observations that MYO6 and LRCH3 both bound to the same site on DOCK7, but MYO6 and DOCK7 bound distinct sites on LRCH3 imply that LRCH3 is the linker between MYO6 and DOCK7. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: A cell-specific proteome-scale network reported an LRCH3-DOCK7 contact at filamentous actin. Reason: This AP-MS edge corroborates partner association but does not independently establish the LRCH3 linker mechanism or septin-remodeling output. Generic protein binding remains uninformative, and the live location extension does not by itself demonstrate direct actin association. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MARK AS OVER ANNOTATED | Summary: Endogenous-tagging cell maps reported LRCH3 associations with DOCK7 and MYO6. Reason: The merged screen partners corroborate the focused DISP-module evidence but do not themselves establish simultaneous bridging or a cellular function. The DOCK7 assertion carries the live filamentous-actin extension; generic protein binding is still less informative than the directly mapped adaptor role. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Multimodal cell maps reported LRCH3 associations with DOCK7 and MYO6. Reason: These dataset-level contacts are compatible with PMID:29467281 but do not independently define LRCH3 molecular activity or a constitutively stable complex. The DOCK7 assertion's filamentous-actin extension is preserved, while generic protein binding remains uninformative. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence supports cytosolic localization of LRCH3. Reason: The direct localization call agrees with the independent cytoplasm annotations and with LRCH3's experimentally studied cytoskeletal role. |
| GO:0031106 septin ring organization | NAS PMID:29467281 The MYO6 interactome reveals adaptor complexes coordinating ... | KEEP AS NON CORE | Summary: LRCH3 and the DOCK7 DHR-2 domain promote assembly of cytosolic septin ring structures. Reason: This NAS assertion comes through ComplexPortal and is supported by ectopic cytosolic septin rings produced by LRCH3 overexpression, strongly enhanced by coexpression of the DOCK7 DHR-2 domain. The gain-of-function morphology is a valid context-specific output but is not established as the normal core form of septin organization. Its parent process GO:0032185 remains core-supported, with the same overexpression caveat retained. Supporting Evidence: PMID:29467281 Strikingly however, the co‐expression of LRCH3 and the DOCK7 DHR2 domain, which contains the LRCH3 and MYO6 binding sites as well as the RAC1/CDC42 GEF activity of DOCK7, caused a very dramatic increase in the number of cells (~80%) containing septin ring structures (Fig 6D). |
| GO:0005737 cytoplasm | IC PMID:29467281 The MYO6 interactome reveals adaptor complexes coordinating ... | ACCEPT | Summary: Cytoplasmic localization is inferred from LRCH3's demonstrated role in septin cytoskeleton organization. Reason: The IC assertion is coherent with the source process evidence and agrees with independent cytosol and cytoplasm localization annotations. Supporting Evidence: PMID:29467281 Overexpression of LRCH3 alone does not lead to any obvious changes in actin filament organisation but led to the displacement of septins from actin filaments and the assembly of cytosolic ring‐like septin structures in a small but significant population of cells (Fig 6B–D). |
| GO:0032185 septin cytoskeleton organization | IMP PMID:29467281 The MYO6 interactome reveals adaptor complexes coordinating ... | ACCEPT | Summary: LRCH3 regulates septin cytoskeleton organization as part of the MYO6-DOCK7-associated DISP module. Reason: The focused study maps LRCH3 interactions, shows CH-region-dependent SEPT7 recruitment, and demonstrates displacement of septins from actin filaments and formation of ring-like structures after LRCH3 expression. The process is the strongest direct cellular function established for LRCH3, although its current support is a gain-of-function phenotype in cultured cells rather than an endogenous loss-of-function demonstration. Supporting Evidence: PMID:29467281 These data provide the first evidence for a possible role of LRCH3 and DOCK7 in the remodelling of the septin cytoskeleton. |
| GO:0032991 protein-containing complex | IDA PMID:29467281 The MYO6 interactome reveals adaptor complexes coordinating ... | NEW | Summary: LRCH3 is part of the experimentally mapped MYO6-LRCH3-DOCK7 DISP complex. Reason: Pull-downs and domain mapping support a trimeric MYO6-LRCH3-DOCK7 complex in the tested human cell systems, with LRCH3 linking MYO6 and DOCK7. GO:0032991 is used pending creation of the specific DOCK7-induced septin displacement complex term proposed below; septins are not asserted as subunits. Supporting Evidence: PMID:29467281 We next confirmed the interactions between MYO6, LRCH3 and DOCK7 and mapped the topology of the complex by performing pull‐down experiments using full‐length and functional domain fragments of LRCH3 and DOCK7. |
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Download this section (compressed HTML)Q: Do endogenous LRCH3, DOCK7, and MYO6 occupy one transient module in human cells, and what signal controls its assembly or disassembly?
Suggested experts: Cytoskeletal trafficking experts, Endogenous interactomics experts
Q: Does LRCH3 regulate DOCK7 exchange activity toward RAC1 or CDC42, or does the DHR-2 interaction serve only to position the GEF?
Suggested experts: DOCK-family signaling experts, Rho GTPase experts
Q: Does the LRCH3 calponin-homology region contact a septin or F-actin directly, and which molecular interface produces septin displacement?
Suggested experts: Septin experts, Actin cytoskeleton experts
Q: Are the four endogenous LRCH3 isoforms differentially expressed or specialized for MYO6, DOCK7, septin, or cleavage-furrow localization?
Suggested experts: Isoform biology experts, Cell-division experts
Experiment: Introduce endogenous fluorescent and affinity tags into all three genes in a human cell type expressing LRCH3, then combine time-resolved proximity labeling, reciprocal native immunoprecipitation, and single-molecule imaging before and during septin reorganization. Use interface-selective LRCH3 mutants to test whether simultaneous partner engagement is required.
Hypothesis: Endogenous LRCH3 transiently bridges MYO6 and DOCK7 during localized septin remodeling rather than forming a constitutive complex.
Type: endogenous interaction dynamics
Experiment: Reconstitute DOCK7 nucleotide exchange with purified LRCH3 domains and RAC1 or CDC42, then measure localized GTPase activity with biosensors in LRCH3-null human cells rescued by wild-type, DOCK7-binding-deficient, or MYO6-binding-deficient LRCH3 at endogenous expression levels.
Hypothesis: LRCH3 binding to the DOCK7 DHR-2 region changes localized RAC1 or CDC42 exchange activity during septin-ring formation.
Type: biochemistry and live-cell signaling
Experiment: Compare purified LRCH3 calponin-homology region binding to reconstituted septin oligomers and F-actin, map any direct interface, and test separation-of-function mutants in endogenous rescue assays that quantify septin displacement, ring formation, and actin organization.
Hypothesis: The LRCH3 calponin-homology region recruits septins through a specific protein interface rather than through direct F-actin binding.
Type: cytoskeletal reconstitution
Experiment: Use long-read RNA sequencing and isoform-specific proteomics across human tissue and cell panels, followed by isoform-specific rescue in an LRCH3-null background to compare partner association, cytosolic and cleavage-furrow localization, and septin-remodeling phenotypes.
Hypothesis: LRCH3 isoforms differ in tissue expression or DISP-module activity.
Type: isoform-resolved functional genomics
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The abundance, dynamics, and cellular contexts of endogenous LRCH3 association with MYO6 and DOCK7 have not been established, and it is unknown whether all three proteins occupy one module simultaneously in unmodified human cells.
OPEN BIOLOGY MF_DARK
Significance: Endogenous measurements are needed to establish when the mapped adaptor topology operates and to avoid treating an expressed-cell module as a constitutive stable complex in every tissue.
Provenance (the field's own admissions):
Gap: The molecular relationship between LRCH3 and septins remains unresolved because septins were not recovered in LRCH3 immunoprecipitates despite proximity and calponin-homology-region-dependent relocalization evidence.
OPEN BIOLOGY MF_DARK
Significance: Determining whether LRCH3 contacts a septin directly or recruits it through an intermediate is necessary to define the immediate activity that drives septin displacement and oligomerization.
Provenance (the field's own admissions):
Gap: It is unknown whether LRCH3 changes DOCK7 guanine-nucleotide exchange activity, substrate choice, or spatial signaling toward RAC1 and CDC42 during septin remodeling.
OPEN BIOLOGY MF_DARK
Significance: The current evidence links LRCH3 to the catalytic DHR-2 region and a cellular phenotype but does not establish whether LRCH3 regulates catalysis or uses the domain only as a recruitment site.
Gap: Direct binding of LRCH3 to F-actin has not been demonstrated, and the actin structure or subcellular site at which endogenous septin remodeling occurs is not defined.
OPEN BIOLOGY MF_DARK
Significance: This distinction is needed to separate a direct cytoskeletal-binding activity from an indirect adaptor role operating near actin-associated septins.
Gap: The expression, localization, and partner specificity of the four LRCH3 splice isoforms have not been compared in endogenous human tissues.
OPEN BIOLOGY RESIDUAL_SUBGAP
Significance: Isoform-resolved evidence would determine whether the DISP-module observations apply broadly or to a restricted LRCH3 product and cellular context.
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