Affinage

GUCA1A

Guanylyl cyclase-activating protein 1 · UniProt P43080

Length
201 aa
Mass
22.9 kDa
Annotated
2026-04-28
84 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GUCA1A encodes GCAP1, a myristoylated neuronal calcium sensor that serves as the principal feedback regulator of retinal guanylyl cyclase (RetGC1) in photoreceptor phototransduction. In light-adapted photoreceptors at low Ca²⁺, Mg²⁺ occupancy of EF-hands 2 and 3 drives GCAP1 into an activator conformation that binds RetGC1 through a surface patch on EF1–EF3 and the cyclase dimerization domain, stimulating cGMP synthesis; Ca²⁺ binding to EF-hand 4 during dark adaptation triggers an allosteric conformational switch that converts GCAP1 into a cyclase inhibitor, with additional inhibition mediated by Ca²⁺-dependent binding of RD3 (PMID:16793776, PMID:17545152, PMID:26703466, PMID:41819313). GCAP1 alone is sufficient to support normal flash response recovery in both rod and cone photoreceptors in vivo (PMID:11927539, PMID:12732716). Dominant mutations in EF-hand Ca²⁺-coordinating residues (e.g., Y99C, E155G, E111V) impair the Ca²⁺-dependent inhibitory switch, rendering RetGC1 constitutively active and causing toxic cGMP accumulation that leads to autosomal dominant cone and cone–rod dystrophies (PMID:9651312, PMID:11484154, PMID:21464903, PMID:30184081).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1994 High

    Identification of GCAP1 as a photoreceptor-specific Ca²⁺-binding protein that stimulates cGMP synthesis established the molecular identity of the guanylyl cyclase activating protein in the phototransduction cascade.

    Evidence Molecular cloning, in situ hybridization, genomic mapping, and in vitro cGMP synthesis assay

    PMID:7983048

    Open questions at the time
    • Mechanism of Ca²⁺-dependent regulation not yet defined
    • Target cyclase identity not confirmed in vivo
    • Role of individual EF-hands unknown
  2. 1998 High

    Demonstrating that the Y99C disease mutation renders GCAP1 constitutively active across the full Ca²⁺ range linked a specific molecular defect—loss of Ca²⁺-dependent inhibition—to dominant cone dystrophy and established the activator-to-inhibitor switch as essential for photoreceptor health.

    Evidence In vitro RetGC reconstitution assays with recombinant Y99C GCAP1 at varying Ca²⁺, replicated independently by two labs

    PMID:9651312 PMID:9702199

    Open questions at the time
    • Structural basis of Y99C effect unknown
    • In vivo consequences not yet demonstrated in animal model
  3. 1999 High

    Fluorescence and kinetic analyses revealed that Ca²⁺ binding triggers a major conformational change near EF3, transitioning GCAP1 from activator to inhibitor, and that the Y99C mutation prevents this transition—establishing the conformational switch mechanism.

    Evidence Site-directed Trp mutagenesis, fluorescence spectroscopy, stopped-flow kinetics, and in vitro GC assays

    PMID:10391927

    Open questions at the time
    • Atomic-resolution structure of activator vs inhibitor states not available
    • Role of Mg²⁺ not yet appreciated
  4. 1999 High

    Mapping two short regions in the RetGC1 juxtamembrane domain as critical for GCAP1-dependent activation began defining the cyclase-side binding interface.

    Evidence Peptide competition and mutagenesis of ROS-GC1 with in vitro cyclase activity readout

    PMID:10571055

    Open questions at the time
    • Full binding interface on both partners undefined
    • Stoichiometry unknown
  5. 2001 High

    Characterization of P50L (haploinsufficiency via protein instability) and E155G (constitutive activation via loss of EF4 Ca²⁺ coordination) established that distinct molecular mechanisms—both affecting Ca²⁺-dependent regulation—underlie different GCAP1 disease alleles.

    Evidence In vitro RetGC activation, CD spectroscopy, protease resistance, and thermal stability assays with recombinant mutants

    PMID:11136713 PMID:11484154

    Open questions at the time
    • In vivo confirmation of E155G mechanism needed
    • P50L mechanism (haploinsufficiency vs. partial constitutive activation) debated
  6. 2002 High

    Transgenic rescue of GCAP1/GCAP2 double-knockout mice by GCAP1 alone demonstrated that GCAP1 is sufficient for normal rod and cone flash response recovery, establishing its non-redundant physiological role in phototransduction feedback.

    Evidence Transgenic GCAP1 expression in GCAPs double-KO mice; ERG and single-cell recordings

    PMID:11927539 PMID:12732716

    Open questions at the time
    • Whether GCAP1 and GCAP2 regulate distinct pools of RetGC remains unresolved
    • Cone-specific vs rod-specific GCAP1 contributions not fully separated
  7. 2006 High

    Identifying Mg²⁺-bound GCAP1 (not the apo form) as the true physiological activator of RetGC1 redefined the activator state and assigned specific roles to Mg²⁺ occupancy at EF-hands 2 and 3.

    Evidence In vitro RetGC1 activation at physiological Mg²⁺/Ca²⁺; Trp fluorescence; EF-hand mutagenesis

    PMID:16793776 PMID:17545152

    Open questions at the time
    • Structural basis of Mg²⁺-induced activation conformation not resolved at atomic level
  8. 2008 High

    Cell-based and FRET studies established that EF-hand 2 metal binding is the primary determinant of GCAP1–RetGC1 association (1:1 stoichiometry), while EF-hand 4 solely mediates the activator-to-inhibitor switch, separating binding from regulation.

    Evidence Live-cell co-localization of EF-hand mutants with RetGC1 in HEK293 cells; FRET stoichiometry; mutagenesis of RetGC1 kinase homology domain

    PMID:18541533 PMID:20050595

    Open questions at the time
    • No high-resolution structure of the GCAP1–RetGC1 complex
  9. 2011 High

    Knock-in E155G mice showing progressive cone-dominant degeneration preceded by cGMP accumulation provided the first in vivo proof that constitutive cyclase activation is the pathogenic mechanism in GCAP1-linked cone–rod dystrophy.

    Evidence Gene-targeted knock-in mouse; ERG; retinal histology; cGMP measurements

    PMID:21464903

    Open questions at the time
    • Therapeutic intervention (e.g., PDE6 modulation or gene therapy rescue) not tested
    • Relative cone vs rod vulnerability mechanism unknown
  10. 2014 High

    Systematic surface mutagenesis mapped the RetGC1-binding site on GCAP1 to a defined patch spanning EF1–EF3 and identified residues (Met-26, Lys-85, Trp-94) required specifically for cyclase activation beyond binding, distinguishing docking from allosteric stimulation.

    Evidence Comprehensive alanine scanning of GCAP1 surface; co-localization and RetGC1 activation in HEK293 cells and in vitro

    PMID:24567338

    Open questions at the time
    • No direct structural visualization of the GCAP1–RetGC1 interface
  11. 2015 High

    NMR structure of Mg²⁺-bound GCAP1 revealed that Ca²⁺-dependent structural changes are concentrated in the EF4 'Ca²⁺-switch helix' (residues 164–174), and domain-swap experiments identified the RetGC1 dimerization domain (Arg-822/Met-823) as essential for GCAP binding, completing the structural framework for the regulatory interaction.

    Evidence NMR with residual dipolar couplings; RetGC1/NPRA chimeras; co-localization and in vitro activation assays

    PMID:26100624 PMID:26703466

    Open questions at the time
    • No co-structure of the GCAP1–RetGC1 complex
    • How the switch helix communicates to the cyclase active site is unclear
  12. 2018 High

    Multiple new disease mutations (E111V, G86R, L176F, N104H) were shown to impair Ca²⁺ sensing through distinct mechanisms—disrupting EF3 coordination, hinge flexibility, or GC affinity—yet all converge on constitutive cyclase activation, consolidating the unified pathogenic model.

    Evidence Recombinant mutant proteins; CD, fluorescence, ITC, limited proteolysis, in vitro RetGC activation assays, and molecular dynamics

    PMID:28025326 PMID:30184081 PMID:30622141 PMID:34639157

    Open questions at the time
    • Genotype-phenotype correlations (cone vs macular dystrophy) not mechanistically explained
    • Inter-EF-hand allosteric coupling quantitatively unresolved
  13. 2020 Medium

    Genetic ablation of GCAPs in rd3 mice substantially delayed photoreceptor death, revealing that Ca²⁺-free GCAP proteins retained in the inner segment cause ER stress and mitochondrial damage—extending the pathogenic role of GCAP1 beyond cGMP toxicity to proteotoxic stress.

    Evidence Double-knockout (rd3 × GCAPs⁻/⁻) mice; ER stress markers; mitochondrial ultrastructure; retinal cell counting

    PMID:31980596

    Open questions at the time
    • Relative contribution of GCAP1 vs GCAP2 to ER stress in rd3 not separated
    • Whether ER stress is upstream or parallel to cGMP-mediated death unclear
  14. 2024 High

    Direct demonstration that Ca²⁺-loaded GCAP1 binds RD3 (KD ~1.6 µM) to form a ternary inhibitory complex with RetGC1, and that the E111V mutation abolishes this interaction, established RD3-mediated inhibition as a second regulatory axis dependent on GCAP1 conformation.

    Evidence SPR, NMR, AlphaFold3 modeling, enzymatic assays, and immunohistochemistry

    PMID:41819313

    Open questions at the time
    • Cryo-EM or crystal structure of the ternary GCAP1–RD3–RetGC1 complex not available
    • Physiological significance of GCAP1–RD3 interaction in intact photoreceptors not tested by genetic manipulation

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of the GCAP1–RetGC1 complex (and the ternary GCAP1–RD3–RetGC1 complex) is needed to understand how the EF4 Ca²⁺-switch helix communicates allosterically to the cyclase catalytic site, and why different GCAP1 mutations cause cone-dominant versus macular dystrophy phenotypes.
  • No co-structure of GCAP1–RetGC1 or GCAP1–RD3–RetGC1 complex
  • Genotype-phenotype correlations for different GCAP1 mutations mechanistically unexplained
  • Therapeutic strategies targeting constitutive cyclase activation untested in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 9 GO:0009975 cyclase activity 3 GO:0140299 molecular sensor activity 3
Localization
GO:0005929 cilium 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-9709957 Sensory Perception 4
Partners
GUCY2DGUCY2FRD3
Complex memberships
GCAP1–RD3–RetGC1 ternary complexGCAP1–RetGC1 complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 GCAP1 Y99C mutation causes constitutive activation of retinal guanylyl cyclase (RetGC): recombinant Y99C GCAP1 fails to inhibit RetGC even at Ca2+ concentrations above 1 µM, rendering the cyclase constitutively active across the entire physiological Ca2+ range. In vitro reconstitution assay of RetGC activity with recombinant Y99C GCAP1 at varying free Ca2+ concentrations The Journal of biological chemistry High 9651312 9702199
1998 GCAP1 (Y99C) mutant is constitutively active: it persistently stimulates GC1 under physiological dark conditions due to markedly altered Ca2+ sensitivity, consistent with elevated cGMP in dark-adapted cones. In vitro GC1 stimulation assay and Ca2+-dependent activity measurements with recombinant GCAP1(Y99C) Molecular cell High 9702199
1994 Human GCAP1 (GUCA1A) is a Ca2+-binding protein with three EF-hand motifs expressed exclusively in photoreceptor inner segments, encoded by a four-exon gene localized to chromosome 6p21.1, and stimulates cGMP synthesis. Molecular cloning, in situ hybridization, genomic mapping by somatic hybrid panel and FISH, in vitro cGMP synthesis assay The Journal of biological chemistry High 7983048
2006 The Mg2+-bound form of GCAP1 (not the cation-free form) is the true physiological activator of RetGC1 in light-adapted photoreceptors; Mg2+ binding in EF-hands 2 and 3 is essential for RetGC1 stimulation. In vitro RetGC1 activation assay at physiological Mg2+/Ca2+ concentrations; tryptophan fluorescence to monitor conformational states; EF-hand mutagenesis The Journal of biological chemistry High 16793776
2007 Mg2+ binding in EF-hand 2 of GCAP1 increases its affinity for RetGC ~40-fold and is essential for cyclase activation; Mg2+ binding in EF-hand 3 enhances stimulation 2-fold; Ca2+ binding in EF-hand 4 triggers the activator-to-inhibitor switch, while EF-hand 3 modulates Ca2+-dependent deceleration indirectly through EF-hand 4. In vitro RetGC1 activation assays with EF-hand mutants; tryptophan fluorescence; Mg2+/Ca2+ competition measurements The Journal of biological chemistry High 17545152
2001 GCAP1 E155G mutation (in EF4 domain) eliminates Ca2+ binding via loss of bidentate coordination, causing constitutive activation of RetGC at high Ca2+ concentrations and autosomal dominant cone dystrophy. In vitro RetGC activation assay with recombinant E155G GCAP1; structural modeling American journal of human genetics High 11484154
1999 Two short regions (M445–L456 and L503–I522) in the juxtamembrane domain (JMD) of ROS-GC1 are critical for GCAP1-dependent activation, identified by peptide competition and mutagenesis. Peptide competition assays and mutagenesis of ROS-GC1 expressed in cells; in vitro cyclase activity measurements FEBS letters High 10571055
2008 Metal binding in EF-hand 2 of GCAP1 is crucial for its binding to RetGC1; EF-hand 3 enhances but is not essential for association; EF-hand 4 mediates only the activator-to-inhibitor switch and is not required for primary cyclase attachment. Co-localization and co-transfection in HEK293 cells with GFP-tagged GCAP1 EF-hand mutants and mOrange-tagged RetGC1; live-cell fluorescence imaging The Journal of biological chemistry High 18541533
2010 RetGC1 binds GCAP1 in an equimolar (1:1) stoichiometry in HEK293 cells; mutations D639Y and R768W in the kinase homology domain of RetGC1 abolish GCAP1 binding and activation, implicating this domain in GCAP1 recognition. FRET-based stoichiometry measurement of fluorescently labeled RetGC1 and GCAP1 co-expressed in HEK293 cells; in vitro reconstitution assay Biochemistry High 20050595
2014 The RetGC1 binding site on GCAP1 is a distinct surface patch formed by EF-hand 1, the loop and exiting helix of EF-hand 2, and the entering helix of EF-hand 3; residues Met-26, Lys-85, and Trp-94 are required for cyclase activation (an additional step beyond binding). Systematic surface mutagenesis of GCAP1; co-localization and RetGC1 activation assays in HEK293 cells; in vitro RetGC1 stimulation assay The Journal of biological chemistry High 24567338
2015 The dimerization domain of RetGC1, especially residues Arg-822 and Met-823, is an essential part of the GCAP1/2 binding interface; disruption at this site (R822P, disease mutation) abolishes GCAP binding but not RD3 binding or cyclase dimerization. RetGC1/NPRA chimera construction; co-expression and co-localization assay in HEK293 cells with GFP-tagged GCAP1; in vitro RetGC1 activation assay; functional complementation tests The Journal of biological chemistry High 26100624
2015 NMR structure of GCAP1(V77E) in Ca2+-free/Mg2+-bound activator state reveals that Mg2+ binds at EF2; Ca2+-dependent structural changes occur specifically in the EF4 Ca2+-switch helix (residues 164–174); deletion or mutation of this helix abolishes RetGC1 activation and reduces Ca2+ binding affinity. NMR spectroscopy with residual dipolar coupling; in vitro RetGC1 activation assays; Ca2+ binding analysis of helix deletion mutants The Journal of biological chemistry High 26703466
2002 GCAP1 alone (in the absence of GCAP2) is sufficient to support wild-type flash responses and recovery kinetics in rod photoreceptors in vivo. Transgenic rescue experiment: GCAP1 expressed under endogenous promoter in GCAP1/GCAP2 double-knockout mice; paired-flash ERG recordings; single-cell recordings The EMBO journal High 11927539
2003 GCAP1 is required for normal cone photoreceptor response recovery; GCAP1/GCAP2 double-knockout mice show delayed cone a-wave and b-wave recovery, and transgenic GCAP1 restores normal cone recovery. ERG recordings (photopic, paired-flash) in GCAP null and GCAP1 transgenic rescue mice; immunohistochemistry Proceedings of the National Academy of Sciences of the United States of America High 12732716
2001 GCAP1 P50L mutation reduces protein stability (increased protease susceptibility, reduced thermal stability) without altering Ca2+ sensitivity or RetGC1 activation, suggesting haploinsufficiency via reduced protein concentration as the disease mechanism. In vitro RetGC1 activation assay; circular dichroism spectroscopy; protease resistance assay; thermal stability assay Human molecular genetics Medium 11136713
2004 GCAP1 I143NT mutation (in EF4) partially inhibits GC at high Ca2+, adopts a protease-susceptible conformation, and results in incomplete inactivation consistent with constitutive GC activation in dark-adapted cones. In vitro RetGC stimulation assay; fluorescence emission spectra; limited proteolysis; immunoblotting Investigative ophthalmology & visual science Medium 15505030
2009 Novel GCAP1 mutations (E89K, D100E, G159V, L151F) alter Ca2+-dependent conformational changes and persistent stimulation of guanylate cyclase at physiological Ca2+ concentrations, while still functioning as Ca2+ sensors. Purified recombinant GCAP1 variants; Ca2+-triggered conformational change assays; apparent interaction affinity with RetGC; Ca2+-dependent activation profiles Human mutation Medium 19459154
2010 All tested disease-associated GCAP1 variants (Y99C, E155G, P50L, I143NT) show decreased Ca2+ affinity and reduced thermal stability; myristoylation increases Ca2+ affinity and thermal stability; non-myristoylated mutants activate ROS-GC1 at nonphysiological Ca2+ concentrations. Ca2+ binding measurements; thermal stability assays; ROS-GC1 activation assays; CD spectroscopy Cellular and molecular life sciences : CMLS Medium 20213926
2012 N-terminal myristoylation of GCAP1 (Gly2) is required for efficient activation of RetGC1 in vitro; the non-myristoylated G2A mutant co-localizes with RetGC1 less efficiently and shifts Ca2+ sensitivity of the cyclase to higher Ca2+ concentrations. Co-localization of GFP-tagged G2A GCAP1 with RetGC1 in HEK293 cells; in vitro RetGC1 activation assay; Ca2+ binding isotherm measurement Frontiers in molecular neuroscience Medium 22371697
1999 Ca2+ binding to GCAP1 causes a major conformational change around the EF3-hand region, transitioning GCAP1 from activator to inhibitor of GC; the Y99C mutation (adjacent to EF3) prevents stabilization of the inactive Ca2+-bound complex; Ca2+ association occurs near diffusion-limit (k1 > 2×10^8 M⁻¹s⁻¹) and dissociation is rapid. Site-directed Trp mutagenesis; fluorescence spectroscopy; stopped-flow kinetics; in vitro GC activity assays The Journal of biological chemistry High 10391927
2019 GCAP1 G86R mutation (in the hinge connecting EF-hands 2 and 3) strongly impairs Ca2+-dependent activator-to-inhibitor conformational transition, activates RetGC with higher affinity at low Ca2+ but fails to decelerate it at dark-adapted Ca2+ concentrations; the mutation also reduces sensitivity of RD3-mediated inhibition of the GCAP1-RetGC1 complex. In vitro RetGC1 activation assay; Trp94 fluorescence; isothermal titration calorimetry; dose-response for RD3 inhibition The Journal of biological chemistry High 30622141
2011 Knock-in mice expressing E155G GCAP1 show progressive cone-dominant photoreceptor degeneration preceded by cGMP accumulation, establishing constitutive guanylate cyclase activation as the disease mechanism in dominant cone-rod dystrophy. Gene targeting/knock-in mouse model; ERG; retinal histology; immunohistochemistry; cGMP level measurements PloS one High 21464903
2017 GCAP1 L176F mutation associated with macular dystrophy causes constitutive activation of guanylate cyclase; the mutant is less sensitive to Ca2+ changes, shows 90-fold higher GC activation than WT (vs 20-fold for WT), binds GC with higher apparent affinity, and binds Mg2+ with higher affinity. In vitro RetGC activation assay; Ca2+/Mg2+ binding measurements; CD spectroscopy; molecular dynamics simulations Human molecular genetics Medium 28025326
2018 GCAP1 E111V mutation disrupts Ca2+ coordination in EF3, reducing Ca2+ affinity ~80-fold; the Mg2+-bound form prone to aggregation; both WT and E111V form dimers; functional assay shows E111V shifts GC inhibition outside physiological Ca2+ range (IC50 ~10 µM), causing constitutive cGMP synthesis. Heterologous expression and purification; circular dichroism; fluorescence spectroscopy; molecular dynamics simulations; in vitro RetGC1 activation assay; analytical gel filtration Human molecular genetics High 30184081
2016 Molecular dynamics simulations reveal that Mg2+/Ca2+ exchange in GCAP1 EF-hands routes allosteric communication pathways that selectively switch GC activation/inhibition; myristoylation mediates long-range allosteric interactions including EF2–EF4 coupling and communication between EF4 and the GC binding interface. Exhaustive molecular dynamics simulations; allosteric pathway analysis Scientific reports Low 27739433
2004 In GC1 knockout mice, GCAP1 protein is specifically downregulated and absent from photoreceptor outer segments (while GCAP2 is less affected), and GC1-GCAP1 interactions are essential for cone cell function. Western blot; Northern blot; immunohistochemistry of GC1 knockout mouse retina Investigative ophthalmology & visual science Medium 15452041
2010 GCAP1 is biochemically and physiologically coupled to the olfactory guanylate cyclase ONE-GC in ciliary membranes, where it acts as an incremental stimulator of ONE-GC in response to rising Ca2+ (nanomolar to semi-micromolar range), reversing its inhibitory role in ROS-GC1 phototransduction signaling. Gene deletion; live-cell FRET; surface plasmon resonance spectroscopy; enzyme activity assays Biochemistry Medium 20684533
2013 NMR analysis of GCAP1 reveals that Ca2+-dependent structural changes are concentrated at EF4 and EF1; residues K23 and G32 in EF1 show large chemical shift differences and their mutation decreases RetGC1 activation, confirming a functional conformational change in EF1. NMR chemical shift assignments of Ca2+-saturated WT vs EF4mut GCAP1; site-directed mutagenesis; in vitro RetGC1 activation assay PloS one Medium 24236217
2020 GCAPs ablation substantially delays photoreceptor cell death in rd3 mice; Ca2+-free GCAP proteins retained at the inner segment in activator conformation induce endoplasmic reticulum stress and mitochondrial swelling, mediating photoreceptor death in LCA12. Genetic double-knockout (rd3 × GCAPs-/-) mice; retinal cell counting; ER stress markers; mitochondrial ultrastructure; phosphorylation state of GCAP2 Cell death & disease Medium 31980596
2021 GCAP1 N104H mutation impairs Ca2+ sensitivity and strongly doubles the affinity for GC (EC50 halved), resulting in constitutive GC hyperactivation; molecular dynamics shows increased flexibility at the GCAP1/GC interface under high Ca2+ conditions. Heterologous expression; circular dichroism; limited proteolysis; dynamic light scattering; in vitro RetGC1 activation assay; molecular dynamics simulations International journal of molecular sciences Medium 34639157
2022 RetGC1 undergoes a two-state allosteric switch between active (R-state, stabilized by Ca2+-free/Mg2+-bound GCAP1) and inactive (T-state, stabilized by Ca2+-bound GCAP1 or RD3) conformations; exposed hydrophobic residues H19, Y22, M26, F73, V77, W94 in GCAP1 are essential for cyclase activation. Structural review integrating NMR data, mutagenesis, and modeling Frontiers in molecular neuroscience Low 36157073
2020 D100G, E155A, and E155G mutations in GCAP1 EF-hands cause constitutive GC activation; all three variants form stable dimers with decreased Ca2+ affinity; mutation of bidentate glutamate in one EF-hand allosterically destabilizes the adjacent EF-hand, suggesting inter-EF-hand allosteric coupling. Recombinant protein expression; circular dichroism; fluorescence spectroscopy; in vitro GC activation assay; molecular dynamics simulations Biochimica et biophysica acta. Molecular cell research Medium 32650103
2024 Wild-type GCAP1 directly interacts with RD3; the interaction is Ca2+-dependent (Ca2+-bound GCAP1 binds RD3 with KD ~1.6 µM, Mg2+-bound GCAP1 much more weakly); the E111V mutation completely abolishes RD3 binding; RD3 inhibits GC1 through dual mechanisms (direct GC1 binding and GCAP1-mediated inhibition); GCAP1-RD3-GC1 co-localize in photoreceptor inner segments and synaptic terminals. Surface plasmon resonance; NMR spectroscopy; AlphaFold3 modeling; enzymatic assays; immunohistochemistry; in vitro reconstitution International journal of biological macromolecules High 41819313

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1. Human molecular genetics 194 9425234
1998 Constitutive activation of photoreceptor guanylate cyclase by Y99C mutant of GCAP-1. Possible role in causing human autosomal dominant cone degeneration. The Journal of biological chemistry 144 9651312
1998 GCAP1 (Y99C) mutant is constitutively active in autosomal dominant cone dystrophy. Molecular cell 125 9702199
1997 Calcium binding, but not a calcium-myristoyl switch, controls the ability of guanylyl cyclase-activating protein GCAP-2 to regulate photoreceptor guanylyl cyclase. The Journal of biological chemistry 120 9162068
2006 Ca2+ and Mg2+ binding properties of GCAP-1. Evidence that Mg2+-bound form is the physiological activator of photoreceptor guanylyl cyclase. The Journal of biological chemistry 102 16793776
2002 GCAP1 rescues rod photoreceptor response in GCAP1/GCAP2 knockout mice. The EMBO journal 93 11927539
2001 Identification and functional consequences of a new mutation (E155G) in the gene for GCAP1 that causes autosomal dominant cone dystrophy. American journal of human genetics 92 11484154
2004 Diversity of guanylate cyclase-activating proteins (GCAPs) in teleost fish: characterization of three novel GCAPs (GCAP4, GCAP5, GCAP7) from zebrafish (Danio rerio) and prediction of eight GCAPs (GCAP1-8) in pufferfish (Fugu rubripes). Journal of molecular evolution 85 15486694
2009 Mutations in the GUCA1A gene involved in hereditary cone dystrophies impair calcium-mediated regulation of guanylate cyclase. Human mutation 69 19459154
2004 A novel mutation (I143NT) in guanylate cyclase-activating protein 1 (GCAP1) associated with autosomal dominant cone degeneration. Investigative ophthalmology & visual science 67 15505030
1999 Regions in vertebrate photoreceptor guanylyl cyclase ROS-GC1 involved in Ca(2+)-dependent regulation by guanylyl cyclase-activating protein GCAP-1. FEBS letters 67 10571055
1994 Molecular characterization of human and mouse photoreceptor guanylate cyclase-activating protein (GCAP) and chromosomal localization of the human gene. The Journal of biological chemistry 62 7983048
2007 Activation and inhibition of photoreceptor guanylyl cyclase by guanylyl cyclase activating protein 1 (GCAP-1): the functional role of Mg2+/Ca2+ exchange in EF-hand domains. The Journal of biological chemistry 61 17545152
1995 GCAP-II: isolation and characterization of the circulating form of human uroguanylin. FEBS letters 61 7589507
2010 Calcium binding, structural stability and guanylate cyclase activation in GCAP1 variants associated with human cone dystrophy. Cellular and molecular life sciences : CMLS 60 20213926
2003 Guanylate cyclase-activating protein (GCAP) 1 rescues cone recovery kinetics in GCAP1/GCAP2 knockout mice. Proceedings of the National Academy of Sciences of the United States of America 59 12732716
2005 A novel GCAP1 missense mutation (L151F) in a large family with autosomal dominant cone-rod dystrophy (adCORD). Investigative ophthalmology & visual science 55 15790869
1997 Structural and functional characterization of retinal calcium-dependent guanylate cyclase activator protein (CD-GCAP): identity with S100beta protein. Biochemistry 53 9369488
1999 Conformational changes in guanylyl cyclase-activating protein 1 (GCAP1) and its tryptophan mutants as a function of calcium concentration. The Journal of biological chemistry 45 10391927
1999 Mapping functional domains of the guanylate cyclase regulator protein, GCAP-2. The Journal of biological chemistry 44 10196158
2006 The crystal structure of GCAP3 suggests molecular mechanism of GCAP-linked cone dystrophies. Journal of molecular biology 43 16626734
2006 Granulocyte and monocyte adsorption apheresis (GCAP) for refractory skin diseases caused by activated neutrophils and psoriatic arthritis: evidence that GCAP removes Mac-1-expressing neutrophils. Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 43 16817789
2008 Binding of guanylyl cyclase activating protein 1 (GCAP1) to retinal guanylyl cyclase (RetGC1). The role of individual EF-hands. The Journal of biological chemistry 42 18541533
2005 Mutation in the gene GUCA1A, encoding guanylate cyclase-activating protein 1, causes cone, cone-rod, and macular dystrophy. Ophthalmology 42 15953638
1995 A new human guanylate cyclase-activating peptide (GCAP-II, uroguanylin): precursor cDNA and colonic expression. Biochimica et biophysica acta 42 8519795
2010 Involvement of the calcium sensor GCAP1 in hereditary cone dystrophies. Biological chemistry 40 20370318
2004 Cone cell survival and downregulation of GCAP1 protein in the retinas of GC1 knockout mice. Investigative ophthalmology & visual science 40 15452041
1997 The human GCAP1 and GCAP2 genes are arranged in a tail-to-tail array on the short arm of chromosome 6 (p21.1). Genomics 39 9119368
1998 Ca2+-dependent conformational changes in bovine GCAP-2. Protein science : a publication of the Protein Society 38 9865963
2016 Allosteric communication pathways routed by Ca2+/Mg2+ exchange in GCAP1 selectively switch target regulation modes. Scientific reports 37 27739433
2008 A novel GCAP1(N104K) mutation in EF-hand 3 (EF3) linked to autosomal dominant cone dystrophy. Vision research 37 18706439
2005 Autosomal dominant cone dystrophy caused by a novel mutation in the GCAP1 gene (GUCA1A). Molecular vision 37 15735604
2001 The destabilization of human GCAP1 by a proline to leucine mutation might cause cone-rod dystrophy. Human molecular genetics 37 11136713
2014 Structural diversity of neuronal calcium sensor proteins and insights for activation of retinal guanylyl cyclase by GCAP1. Frontiers in molecular neuroscience 35 24672427
2015 Dimerization Domain of Retinal Membrane Guanylyl Cyclase 1 (RetGC1) Is an Essential Part of Guanylyl Cyclase-activating Protein (GCAP) Binding Interface. The Journal of biological chemistry 33 26100624
2019 A G86R mutation in the calcium-sensor protein GCAP1 alters regulation of retinal guanylyl cyclase and causes dominant cone-rod degeneration. The Journal of biological chemistry 32 30622141
2014 Identification of target binding site in photoreceptor guanylyl cyclase-activating protein 1 (GCAP1). The Journal of biological chemistry 31 24567338
1996 Expression of GCAP1 and GCAP2 in the retinal degeneration (rd) mutant chicken retina. FEBS letters 31 8641465
2017 Dysfunction of cGMP signalling in photoreceptors by a macular dystrophy-related mutation in the calcium sensor GCAP1. Human molecular genetics 30 28025326
2010 GCAP1 mutations associated with autosomal dominant cone dystrophy. Advances in experimental medicine and biology 30 20238026
2018 A novel p.(Glu111Val) missense mutation in GUCA1A associated with cone-rod dystrophy leads to impaired calcium sensing and perturbed second messenger homeostasis in photoreceptors. Human molecular genetics 29 30184081
2013 Novel GUCA1A mutations suggesting possible mechanisms of pathogenesis in cone, cone-rod, and macular dystrophy patients. BioMed research international 28 24024198
2010 Activation of retinal guanylyl cyclase RetGC1 by GCAP1: stoichiometry of binding and effect of new LCA-related mutations. Biochemistry 28 20050595
2015 Two retinal dystrophy-associated missense mutations in GUCA1A with distinct molecular properties result in a similar aberrant regulation of the retinal guanylate cyclase. Human molecular genetics 27 26358777
2013 Structural analysis of guanylyl cyclase-activating protein-2 (GCAP-2) homodimer by stable isotope-labeling, chemical cross-linking, and mass spectrometry. Journal of the American Society for Mass Spectrometry 26 24026978
2013 Disease progression in autosomal dominant cone-rod dystrophy caused by a novel mutation (D100G) in the GUCA1A gene. Documenta ophthalmologica. Advances in ophthalmology 26 24352742
2017 Cone dystrophy or macular dystrophy associated with novel autosomal dominant GUCA1A mutations. Molecular vision 24 28442884
2015 Structure of Guanylyl Cyclase Activator Protein 1 (GCAP1) Mutant V77E in a Ca2+-free/Mg2+-bound Activator State. The Journal of biological chemistry 24 26703466
2007 Characterization of the myristoyl lipid modification of membrane-bound GCAP-2 by 2H solid-state NMR spectroscopy. Biochimica et biophysica acta 24 17936244
1998 Differential activation of rod outer segment membrane guanylate cyclases, ROS-GC1 and ROS-GC2, by CD-GCAP and identification of the signaling domain. Biochemical and biophysical research communications 24 9439621
2017 GUCA1A mutation causes maculopathy in a five-generation family with a wide spectrum of severity. Genetics in medicine : official journal of the American College of Medical Genetics 21 28125083
2001 Identification of functional regions of guanylate cyclase-activating protein 1 (GCAP1) using GCAP1/GCIP chimeras. Biological chemistry 21 11592399
2013 Structural insights for activation of retinal guanylate cyclase by GCAP1. PloS one 19 24236217
2014 Impact of cone dystrophy-related mutations in GCAP1 on a kinetic model of phototransduction. Cellular and molecular life sciences : CMLS 18 24566882
2011 Dominant cone-rod dystrophy: a mouse model generated by gene targeting of the GCAP1/Guca1a gene. PloS one 18 21464903
2019 Normal GCAPs partly compensate for altered cGMP signaling in retinal dystrophies associated with mutations in GUCA1A. Scientific reports 16 31882816
2014 RNA interference gene therapy in dominant retinitis pigmentosa and cone-rod dystrophy mouse models caused by GCAP1 mutations. Frontiers in molecular neuroscience 16 24778606
2013 RNAi-mediated gene suppression in a GCAP1(L151F) cone-rod dystrophy mouse model. PloS one 16 23472098
2004 Ca(2+)-dependent conformational changes in guanylyl cyclase-activating protein 2 (GCAP-2) revealed by site-specific phosphorylation and partial proteolysis. The Journal of biological chemistry 16 15448139
2014 GUCY2D- or GUCA1A-related autosomal dominant cone-rod dystrophy: is there a phenotypic difference? Retina (Philadelphia, Pa.) 15 24875811
2013 Novel GUCA1A mutation identified in a Chinese family with cone-rod dystrophy. Neuroscience letters 14 23428504
2020 Neuronal Calcium Sensor GCAP1 Encoded by GUCA1A Exhibits Heterogeneous Functional Properties in Two Cases of Retinitis Pigmentosa. ACS chemical neuroscience 12 32298085
2016 GCAP1, Rab6, and HSP27: Novel Autoantibody Targets in Cancer-Associated Retinopathy and Autoimmune Retinopathy. Translational vision science & technology 12 27152249
2020 Modulation of Guanylate Cyclase Activating Protein 1 (GCAP1) Dimeric Assembly by Ca2+ or Mg2+: Hints to Understand Protein Activity. Biomolecules 11 33027977
2017 CaF2 nanoparticles as surface carriers of GCAP1, a calcium sensor protein involved in retinal dystrophies. Nanoscale 11 28785759
2012 Interaction of GCAP1 with retinal guanylyl cyclase and calcium: sensitivity to fatty acylation. Frontiers in molecular neuroscience 11 22371697
2021 A Novel GUCA1A Variant Associated with Cone Dystrophy Alters cGMP Signaling in Photoreceptors by Strongly Interacting with and Hyperactivating Retinal Guanylate Cyclase. International journal of molecular sciences 10 34639157
2020 GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress. Cell death & disease 10 31980596
2010 Ca(2+) sensor GCAP1: A constitutive element of the ONE-GC-modulated odorant signal transduction pathway. Biochemistry 10 20684533
2019 Characterization of GUCA1A-associated dominant cone/cone-rod dystrophy: low prevalence among Japanese patients with inherited retinal dystrophies. Scientific reports 9 31728034
2020 Missense mutations affecting Ca2+-coordination in GCAP1 lead to cone-rod dystrophies by altering protein structural and functional properties. Biochimica et biophysica acta. Molecular cell research 8 32650103
2018 Molecular Details of Retinal Guanylyl Cyclase 1/GCAP-2 Interaction. Frontiers in molecular neuroscience 8 30283299
2022 Structural basis of retinal membrane guanylate cyclase regulation by GCAP1 and RD3. Frontiers in molecular neuroscience 6 36157073
2020 Constitutive Activation of Guanylate Cyclase by the G86R GCAP1 Variant Is Due to "Locking" Cation-π Interactions that Impair the Activator-to-Inhibitor Structural Transition. International journal of molecular sciences 6 31979372
2006 Granulocytapheresis (GCAP) for severe alcoholic hepatitis-A preliminary report. Hepatology research : the official journal of the Japan Society of Hepatology 6 16949861
2021 Impaired Ca2+ Sensitivity of a Novel GCAP1 Variant Causes Cone Dystrophy and Leads to Abnormal Synaptic Transmission Between Photoreceptors and Bipolar Cells. International journal of molecular sciences 5 33919796
2023 Access to High-Purity 7m G-cap RNA in Substantial Quantities by a Convenient All-Chemical Solid-Phase Method. Chembiochem : a European journal of chemical biology 4 37666794
2012 Backbone (1)H, (13)C, and (15)N resonance assignments of guanylyl cyclase activating protein-1, GCAP1. Biomolecular NMR assignments 4 22392341
2004 Dominant cone and cone-rod dystrophies: functional analysis of mutations in retGC1 and GCAP1. Novartis Foundation symposium 3 14750595
2019 Functional characterization of a novel GUCA1A missense mutation (D144G) in autosomal dominant cone dystrophy: A novel pathogenic GUCA1A variant in COD. Molecular vision 2 32025184
2002 p19 detected in the rat retina and pineal gland is a guanylyl cyclase-activating protein (GCAP). Acta biochimica Polonica 2 12545196
2024 Supramolecular complexes of GCAP1: implications for inherited retinal dystrophies. International journal of biological macromolecules 1 39187109
2002 Characterisation of two genes for guanylate cyclase activator protein (GCAP1 and GCAP2) in the Japanese pufferfish, Fugu rubripes. Biochimica et biophysica acta 1 12151097
2026 Structural and functional investigation of RD3-GCAP1 interaction in retinal photoreceptors under normal and disease conditions. International journal of biological macromolecules 0 41819313