LRCH2 is a poorly characterized cytoplasmic-facing protein built from an N-terminal leucine-rich-repeat region and a C-terminal calponin-homology domain. In heterologous MDCK and HEK293T expression systems, its leucine-rich repeats associate with DOCK8 and recruit DOCK8 toward the cell periphery, while its calponin-homology region shows cytochalasin-sensitive peripheral and actin-associated localization. These observations connect LRCH2 to spatial organization of a Rho guanine-nucleotide exchange factor, but they do not establish direct actin binding, regulation of DOCK8 catalytic activity, or a physiological cellular output. LRCH2 is expressed in Schwann-lineage cells and developing cerebellar cortex, and a p.Lys258Glu substitution was reported as a candidate in one family with congenital cerebellar hypoplasia and demyelinating polyneuropathy; the molecular effect and gene-disease relationship remain unresolved. Two splice isoforms are described, without demonstrated endogenous functional specialization.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | MARK AS OVER ANNOTATED | Summary: A mammalian Hippo-pathway interaction screen reported an LRCH2-DOCK8 contact. Reason: The IntAct IPI assertion preserves a screen-level physical association with DOCK8, but the abstract-only paper does not expose an LRCH2-specific functional consequence and GO:0005515 is not an informative molecular activity. The DOCK8-inhibitory mechanism established for LRCH1 must not be transferred to LRCH2 from this contact. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: The BioPlex 2.0 affinity-purification network reported an LRCH2-DOCK8 co-association. Reason: This proteome-scale AP-MS record supports physical proximity or co-association in the tested human cell system but does not establish a direct interaction or a regulatory effect on DOCK8. Generic protein binding therefore overstates the functional information available for LRCH2. |
| GO:0005515 protein binding | IPI PMID:32203420 Systems analysis of RhoGEF and RhoGAP regulatory proteins re... | MARK AS OVER ANNOTATED | Summary: A family-wide RhoGEF/RhoGAP interactome study reported an LRCH2-DOCK8 association. Reason: The focused Rho-regulator survey makes the DOCK8 contact biologically relevant, but the accessible abstract does not demonstrate that LRCH2 alters DOCK8 nucleotide-exchange activity, GTPase signaling, or a cellular process. Retaining the dataset provenance does not justify generic protein binding as an informative LRCH2 activity or transfer of the LRCH1 mechanism. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Cell-line-specific proteome-scale interaction maps reported an LRCH2-DOCK8 co-association. Reason: BioPlex 3.0 is a large AP-MS interaction resource, and this dataset-level edge does not establish a direct biochemical activity or stable LRCH2-DOCK8 complex. GO:0005515 is uninformative, and the contact alone cannot support DOCK8 GEF inhibition or immune-cell functions for LRCH2. |
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Download this section (compressed HTML)Q: Does endogenous LRCH2 alter DOCK8 exchange activity toward Cdc42 or another Rho GTPase, or does it act only as a localization factor?
Suggested experts: DOCK-family signaling experts, Rho GTPase experts
Q: Does the LRCH2 calponin-homology domain bind F-actin directly, and which peripheral cellular structure contains endogenous LRCH2?
Suggested experts: Cytoskeleton experts, Cell-biological imaging experts
Q: Which human tissues and cell states express each LRCH2 isoform, and do the isoforms differ in DOCK8 or TEX11 association?
Suggested experts: Isoform biology experts, Human tissue-expression experts
Q: Does p.Lys258Glu disrupt the LRCH2 leucine-rich-repeat fold or DOCK8 recruitment, and does LRCH2 variation reproducibly cause cerebellar and peripheral-nerve disease?
Suggested experts: Neurogenetics experts, Structural biologists
Experiment: Reconstitute DOCK8 nucleotide exchange with purified Cdc42, full-length LRCH2, LRCH1 as a positive comparator, and LRR-deletion variants. In parallel, edit an endogenous epitope tag into LRCH2 and DOCK8 in a human cell type that naturally expresses both proteins and quantify their localization and interaction before and after acute LRCH2 depletion.
Hypothesis: LRCH2 regulates DOCK8 spatially but does not reproduce the DOCK8 catalytic inhibition attributed to LRCH1.
Type: comparative biochemistry and endogenous cell biology
Experiment: Test purified full-length LRCH2 and its isolated calponin-homology domain in F-actin co-sedimentation and quantitative binding assays, then rescue LRCH2-null cells with interface mutants and measure endogenous DOCK8 recruitment using super-resolution live-cell imaging.
Hypothesis: The LRCH2 calponin-homology domain binds actin directly and anchors LRCH2-DOCK8 at an actin-rich peripheral structure.
Type: cytoskeletal biochemistry and imaging
Experiment: Combine long-read RNA sequencing, isoform-specific targeted proteomics, and endogenous proximity labeling in human Schwann-lineage and cerebellar cell models, followed by isoform-specific rescue to compare localization, DOCK8 association, and Rho-GTPase activity.
Hypothesis: LRCH2 isoforms have distinct tissue distributions or interaction profiles.
Type: isoform-resolved proteomics
Experiment: Compare wild-type and p.Lys258Glu LRCH2 for folding, stability, DOCK8 interaction, peripheral recruitment, and downstream Rho-GTPase activity in isogenic human Schwann-cell and cerebellar-lineage models, while pursuing segregation and replication in additional affected families.
Hypothesis: The p.Lys258Glu substitution impairs the LRR-dependent recruitment of DOCK8.
Type: variant functional analysis
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: It is unknown whether LRCH2 changes the guanyl-nucleotide exchange activity, substrate selection, or signaling output of DOCK8 rather than only recruiting expressed DOCK8 toward the cell periphery.
OPEN BIOLOGY MF_DARK
Significance: This is the central missing evidence needed to assign a molecular activity and distinguish LRCH2 from the inhibitory DOCK8 mechanism of LRCH1.
Gap: Direct binding of human LRCH2 to actin has not been demonstrated, and the contribution of its calponin-homology domain to endogenous localization and function is unknown.
OPEN BIOLOGY MF_DARK
Significance: Cytochalasin-sensitive association of an expressed domain does not distinguish direct actin binding from indirect recruitment to an actin-dependent peripheral structure.
Gap: The native cell types, subcellular sites, and physiological processes that use the LRCH2-DOCK8 association have not been established with endogenous proteins.
OPEN BIOLOGY BP_DARK
Significance: Endogenous evidence is required before heterologous recruitment can be connected to Rho-family GTPase signaling, cytoskeletal organization, migration, or another cellular process.
Gap: The expression, localization, and partner specificity of LRCH2 isoforms 1 and 2 have not been compared in endogenous human tissues.
OPEN BIOLOGY RESIDUAL_SUBGAP
Significance: Isoform-resolved evidence would show whether the observed DOCK8 recruitment is shared and whether the reported isoform-2 TEX11 contact has physiological meaning.
Gap: The effect of the reported p.Lys258Glu leucine-rich-repeat substitution on LRCH2 folding, DOCK8 recruitment, cellular behavior, and human disease risk is unknown.
OPEN BIOLOGY BP_DARK
Significance: Functional and genetic replication are needed to move from a single-family candidate association to a mechanistic gene-disease relationship.
Provenance (the field's own admissions):
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