GUCY2D

Reason: AN5 inheritance is intact. Intracellular GCAP regulation and reported natriuretic nonresponse do not settle peptide receptor activity; original ligand-testing details remain inaccessible. The definition also permits intracellular peptides.

Reason: Human photoreceptor outer-segment localization is explicitly reported in the original abstract; retain the curator’s experimentally supported placement.

Reason: Human RetGC1 expressed in HEK293 membranes converted radiolabeled GTP to cGMP; wild-type controls established the catalytic activity.

Reason: Human RetGC1 directly converted GTP to cGMP. Chimeric and mutant assays additionally distinguished catalytic activity from GCAP docking.

Reason: Recombinant human RetGC showed regulated cyclase activity in the original abstract; independent human-protein assays corroborate this established function.

Reason: Wild-type human RetGC1 showed GCAP-stimulated guanylate cyclase activity; adenylyl cyclase activity required engineered substrate-specificity substitutions.

Reason: AN5 inheritance is supported by measured human RetGC1 GTP-to-cGMP conversion, preserving catalytic rather than regulator identity.

Reason: The recombinant human cyclase produced cGMP in HEK293 membrane assays; RD3 inhibited its basal and GCAP-stimulated activity.

Reason: Wild-type human GC-E activity was measured by cGMP production in HEK293T membranes. Constitutive activity of V902L is a mutant phenotype.

Reason: This GCAP3 study directly assayed recombinant human GC1 and quantified its cGMP production by HPLC.

Reason: Human wild-type RetGC1 directly catalyzes cGMP synthesis; the convergent electronic assignments capture its central enzymatic function.

Reason: Retain established guanylate cyclase activity. The abstract reports a mutation that impairs it; independent human RetGC1 assays directly establish catalysis.

Reason: Reactome explicitly places human Q02846 in the catalyst set converting GTP to cGMP.

Reason: The mapped kinase-like domain does not settle phosphotransferase activity. Purified bovine retinal cyclase showed kinase activity, but intrinsic activity was not established by domain mutagenesis; direct human GUCY2D phosphotransferase evidence remains unresolved.

Reason: Human GC1 and RD3 specifically coimmunoprecipitated. Retain this supported interaction as non-core; it does not establish an additional specific molecular function for GUCY2D.

Reason: Human GC1 coimmunoprecipitated with mouse Ankmy2 in HEK293 cells. Retain this supported interaction as non-core, preserving the tested species pair; the association does not establish a more specific molecular function for GUCY2D.

Reason: ATP binding is supported by bovine cyclase photoaffinity labeling and compatible human RetGC1 nucleotide responses; retain this regulatory interaction without asserting kinase catalysis or a directly mapped human binding site. ATP-stimulation evidence is supplementary; direct binding remained speculative in that study.

Reason: Remove the compartment prediction: broad FunFam/taxon membership does not establish nuclear-envelope residence, and the curated location is photoreceptor outer-segment membrane. Training-source dependency is unknown; removal does not assert experimental exclusion of every nuclear-envelope pool.

Reason: The cited original measures retinal transcript layers and bovine outer-segment proteins, not nuclear-envelope localization. Its outer nuclear layer does not support this compartment annotation.

Reason: Wild-type human GC-E showed ER staining after HEK293T transfection. This positive heterologous observation does not establish endogenous photoreceptor ER-membrane residence required by organelle rule 7.

Reason: The electronic ER assignment inherits the same transfected-cell observation. It overstates physiological ER-membrane localization; the observed staining is retained.

Reason: Accepted GO:0042622 preserves the same unextended is_active_in context and entails this broader location through a verified is_a/part_of path.

Reason: Accepted GO:0042622 preserves the same unextended located_in context and entails this broader location through the verified is_a/part_of path.

Reason: The broad plasma-membrane placement is less informative than retained photoreceptor membrane annotations. The recorded ontology path includes part_of; this is not new localization evidence.

Reason: AN5 inheritance agrees with the target's catalytic production of cGMP; the enzyme performs this biosynthetic step.

Reason: Mouse RetGC1-dependent cGMP production in outer-segment preparations supports this conserved biosynthetic role.

Reason: AN5 inheritance is intact, but intracellular GCAP regulation does not establish the required extracellular ligand initiation. Original ligand-testing details remain inaccessible.

Reason: This pathway requires extracellular-ligand initiation. The abstract reports no response to tested natriuretic peptides; full-text access and any supporting ligand evidence remain unresolved.

Reason: The human pedigree showed segregation of the complex GUCY2D allele with visual and electroretinographic abnormalities, supporting its established role in vision.

Reason: Keep the established visual role. The paper links deficient cyclase regulation to phototransduction; human clinical segregation independently supports involvement in vision.

Reason: Retained cGMP biosynthetic process is an is_a descendant of this broader cyclic-nucleotide biosynthetic process.

Reason: The retained guanylate cyclase activity is an is_a descendant of this broader phosphorus-oxygen lyase activity.

Reason: GUCY2D restores cGMP through calcium-sensitive feedback, contributing directly to photoreceptor response recovery.

Reason: Accept the established photoreceptor feedback function and curator-assigned visual context. The abstract links disrupted CRM1 regulation to phototransduction; full methods and construct species remain unverified.

Reason: The pathway contains the Q02846-catalyzed cGMP-restoration reaction, establishing direct enzymatic participation in phototransduction recovery.

Reason: Production of the intracellular messenger cGMP is a direct signaling activity of GUCY2D, not merely an indirect expression response.

Reason: The cloning study establishes cyclase activity, but its available abstract does not resolve the broader signaling-receptor assertion. Full original methods remain unavailable.

Reason: AN230 supports inherited activity location. Rat outer-segment plasma-membrane labeling and native mouse RetGC1 catalysis provide complementary grounding in distinct preparations.

Reason: Human outer-segment localization and recombinant cyclase activity support the curator’s membrane assignment. The unavailable full text limits detailed assay reconstruction.

Reason: Rodent donor activity and localization support outer-segment membranes; internal disc localization remains separately represented.

Reason: Retained homodimerization is an is_a descendant of identical protein binding and provides the specific positive interaction.

Reason: Homodimerization supports cyclase assembly; actual rat donor association experiments ground the conserved function.

Reason: Homodimerization supports cyclase assembly; actual rat donor association experiments ground the conserved function.

Reason: Retained cGMP biosynthetic process is an is_a descendant of cGMP metabolic process.

Reason: Rat GC-E/GC-F heteromer association was demonstrated in COS7; native bovine preparations preferentially contained homomers but retained some heteromers. Preserve the positive noncore interaction.

Reason: Independent human Reactome modeling places Q02846 in photoreceptor disc membrane.

Reason: The actual human Q02846 catalyst-set member is localized to photoreceptor disc membrane; the reaction metabolites being cytosolic do not change this protein compartment.

Reason: Rat donor immunogold microscopy directly places GC-E on rod disc membranes; retain the conserved specific localization.

Reason: The curated UniProt record explicitly attributes human cone outer-segment localization to this paper. Accept the established activity location with curator deference; original microscopy remains uninspected.