acgA

UniProt ID: Q03101
Organism: Dictyostelium discoideum
Review Status: COMPLETE
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Gene Description

acgA encodes adenylyl cyclase G (ACG), an atypical, receptor-type adenylyl cyclase of the class-4 adenylyl/guanylyl cyclase family. It is a single-pass type II membrane protein comprising a large extracellular domain (including a CHASE domain), a single transmembrane anchor, and a single intracellular catalytic cyclase domain that converts ATP to 3',5'-cyclic AMP. ACG is catalytically active as a dimer and, unlike the aggregation-stage cyclase ACA, is insensitive to G proteins. Its defining feature is an intramolecular osmosensor that directly couples high osmolality to cAMP synthesis, a property retained even when ACG is expressed heterologously in yeast. ACG is expressed predominantly in prespore and spore cells. In the fruiting body, the ambient high osmolality of the spore head activates ACG, and the resulting intracellular cAMP maintains high protein kinase A (PKA) activity that keeps spores dormant and prevents premature germination. Earlier in development ACG protein accumulates in the prespore region, where the cAMP it produces promotes prespore differentiation, a role partially redundant with the cyclase ACB (AcrA). ACG function in spore dormancy and germination is deeply conserved across the Dictyostelia and is thought to derive from an ancestral drought/osmolarity-sensing role in the encystation and excystation of solitary amoebae. ACG-dependent cAMP production also participates in SDF-1 phosphopeptide signaling during terminal differentiation; direct binding of SDF-1 to ACG remains unresolved.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005886 plasma membrane
IBA
GO_REF:0000033
ACCEPT
Summary: Phylogenetic inference of plasma membrane localization is consistent with the experimentally determined localization of ACG at the cell periphery of spores and its status as a single-pass type II membrane protein.
Reason: ACG is a transmembrane receptor-type cyclase and is directly observed at the cell periphery in spores, so plasma membrane localization is correct and the IBA inference is supported by direct evidence for this gene.
Supporting Evidence:
PMID:17267449
In spores, ACG was localized at the cell periphery as would be expected for a transmembrane osmosensor
GO:0004016 adenylate cyclase activity
IBA
GO_REF:0000033
ACCEPT
Summary: Adenylate cyclase activity is the core catalytic function of ACG and is directly demonstrated experimentally, so the phylogenetic inference is well supported.
Reason: ACG catalyzes ATP to cAMP conversion (EC 4.6.1.1) and this activity is directly measured; the IBA inference is corroborated by direct evidence.
Supporting Evidence:
PMID:8798577
ACG activity, measured in aca-/ACG cells, was strongly stimulated by high osmolarity with optimal stimulation occurring at 200 milliosmolar.
GO:0001653 peptide receptor activity
IBA
GO_REF:0000033
UNDECIDED
Summary: ACG is an established osmosensor and a candidate receptor or downstream effector for the SDF-1 phosphopeptide; osmosensing alone does not exclude peptide receptor activity.
Reason: PTHR11920-paint.tsv places peptide receptor activity at PTN000229249. The table separately blocks guanylyl cyclase activity, cGMP biosynthesis and receptor guanylyl-cyclase signaling at the Dictyostelia node PTN000938100, but does not record a peptide-receptor loss there. Target PMID:21602484 places ACG in SDF-1 signaling. This does not prove direct SDF-1 binding, and ACG osmoactivation in yeast does not disprove a second ligand-dependent activation mechanism. The former over-annotation verdict was too confident; adjudication should evaluate whether ACG itself recognizes SDF-1. The completed OpenScientist report recommends removal/NOT but explicitly overlooks PMID:21602484: it claims no primary SDF-1/ACG link, whereas this paper places ACG in the SDF-1 signaling cascade. The report correctly summarizes intramolecular osmosensing and NPR-derived peptide-receptor evidence, but neither fact proves loss of peptide recognition; PTN000229249 is an ancestral node in PTHR11920, not a family identifier. Explicit guanylyl-function IRDs at PTN000938100 cannot be extended to peptide receptor activity. Retain UNDECIDED: the remaining issue is direct ligand recognition versus downstream cyclase action, requiring source-level expert follow-up rather than another duplicate report.
Propagation Review
Root cause: UNRESOLVED
Sources checked:
PANTHER:PTN000229249 Β· PTN000229249 UNRESOLVED
The cached PAINT IBD at this node was checked. ACG is an established osmosensor and a candidate receptor or downstream effector for the SDF-1 phosphopeptide; osmosensing alone does not exclude peptide receptor activity. The prior categorical propagation-error assignment is withdrawn pending assessment of retention versus target-specific divergence.
Supporting Evidence:
PMID:14718564
This strongly suggests that the ACG osmosensor is intramolecular, which would define ACG as the first characterized primary osmosensor in eukaryotes.
PMID:21602484
SDF-1 apparently acts through the adenylyl cyclase ACG to activate the cyclic AMP (cAMP)-dependent protein kinase A (PKA) and trigger the production of more SDF-1.
GO:0004016 adenylate cyclase activity
IEA
GO_REF:0000120
ACCEPT
Summary: Electronic assignment of adenylate cyclase activity via EC 4.6.1.1 mapping is correct and matches the experimentally established catalytic function of ACG.
Reason: ACG is a bona fide adenylate cyclase (ATP = cAMP + diphosphate); the IEA/EC-based inference agrees with direct evidence.
Supporting Evidence:
PMID:8798577
an atypical adenylyl cyclase, ACG, in mature spores
GO:0005886 plasma membrane
IEA
GO_REF:0000117
ACCEPT
Summary: ARBA electronic inference of plasma membrane localization is consistent with the direct observation of ACG at the spore cell periphery.
Reason: Plasma membrane localization is supported by direct evidence for ACG in spores; the electronic annotation is correct.
Supporting Evidence:
PMID:17267449
In spores, ACG was localized at the cell periphery as would be expected for a transmembrane osmosensor
GO:0007165 signal transduction
IEA
GO_REF:0000117
KEEP AS NON CORE
Summary: ACG participates in cAMP-mediated signaling, so signal transduction is correct but very general; more specific terms (osmosensory signaling pathway, cAMP biosynthetic process) better capture its role.
Reason: Signal transduction is a broad parent process that is accurate for a cAMP-producing osmosensor but is not informative as a core function.
Supporting Evidence:
PMID:8798577
These data indicate that ACG is an osmosensor controlling spore germination through activation of protein kinase A.
GO:0009190 cyclic nucleotide biosynthetic process
IEA
GO_REF:0000002
MODIFY
Summary: ACG synthesizes the cyclic nucleotide cAMP. The specific child term cAMP biosynthetic process more precisely captures this function than the general cyclic nucleotide biosynthetic process.
Reason: ACG produces cAMP specifically (not cGMP), so the more specific cAMP biosynthetic process is the appropriate term.
Proposed replacements: cAMP biosynthetic process
Supporting Evidence:
PMID:18640994
The osmolyte-activated adenylate cyclase, ACG, produces cAMP for prespore differentiation and inhibition of spore germination.
GO:0016020 membrane
IEA
GO_REF:0000044
KEEP AS NON CORE
Summary: Membrane localization is correct but redundant with the more specific plasma membrane annotation.
Reason: ACG is an integral membrane protein; the general term membrane is subsumed by the more informative plasma membrane annotation.
Supporting Evidence:
PMID:17267449
ACG was localized at the cell periphery as would be expected for a transmembrane osmosensor
GO:0016849 phosphorus-oxygen lyase activity
IEA
GO_REF:0000002
MODIFY
Summary: Phosphorus-oxygen lyase activity is the general parent of adenylate cyclase activity. It is technically correct but the specific child term is more informative.
Reason: ACG's phosphorus-oxygen lyase activity is specifically adenylate cyclase activity; the more specific term should be used.
Proposed replacements: adenylate cyclase activity
Supporting Evidence:
PMID:8798577
ACG activity, measured in aca-/ACG cells, was strongly stimulated by high osmolarity with optimal stimulation occurring at 200 milliosmolar.
GO:0035556 intracellular signal transduction
IEA
GO_REF:0000002
KEEP AS NON CORE
Summary: ACG produces intracellular cAMP that activates PKA, so intracellular signal transduction is accurate but general.
Reason: This is a broad parent process; the intracellular messenger role of ACG-derived cAMP is better captured by cAMP biosynthetic process and the specific developmental/germination processes.
Supporting Evidence:
PMID:8798577
These data indicate that ACG is an osmosensor controlling spore germination through activation of protein kinase A.
GO:0019887 protein kinase regulator activity
IMP
PMID:8798577
Adenylyl cyclase G, an osmosensor controlling germination of...
MARK AS OVER ANNOTATED
Summary: ACG activates PKA, but it does so indirectly by synthesizing the second messenger cAMP that binds the PKA regulatory subunit. ACG is not itself a direct protein kinase regulator; its molecular function is adenylate cyclase activity, and PKA activation is a downstream consequence.
Reason: The IMP phenotype (loss of osmotic control of germination via PKA) reflects ACG acting upstream of PKA through cAMP, not a direct kinase-regulator molecular function. Assigning protein kinase regulator activity conflates the downstream signaling effect with ACG's true catalytic activity.
Supporting Evidence:
PMID:8798577
These data indicate that ACG is an osmosensor controlling spore germination through activation of protein kinase A.
GO:0007165 signal transduction
IMP
PMID:21602484
The polyketide MPBD initiates the SDF-1 signaling cascade th...
KEEP AS NON CORE
Summary: In the SDF-1 signaling cascade, SDF-1 acts through ACG to activate PKA and amplify SDF-1 production. This supports a signal transduction role, though the term is general.
Reason: ACG's involvement in the SDF-1 relay is a genuine but pleiotropic signaling role; signal transduction is too general to be a core function.
Supporting Evidence:
PMID:21602484
SDF-1 apparently acts through the adenylyl cyclase ACG to activate the cyclic AMP (cAMP)-dependent protein kinase A (PKA) and trigger the production of more SDF-1.
GO:0030435 sporulation resulting in formation of a cellular spore
IDA
PMID:17267449
cAMP production by adenylyl cyclase G induces prespore diffe...
KEEP AS NON CORE
Summary: ACG protein is upregulated in prespore tissue and acg null mutants show reduced prespore differentiation, establishing a role in the sporulation program. This role is partly redundant with ACB.
Reason: ACG contributes to prespore differentiation and hence sporulation, but this is a developmental/process role downstream of its catalytic and osmosensing molecular functions and is partially redundant with ACB.
Supporting Evidence:
PMID:17267449
acg null mutants show reduced prespore differentiation, which becomes very severe when ACB is also deleted.
PMID:17267449
These data show that ACG induces prespore differentiation in wild-type cells, with ACB capable of partially taking over this function in its absence.
GO:0009992 intracellular water homeostasis
IDA
PMID:14718564
Adenylyl cyclase G is activated by an intramolecular osmosen...
UNDECIDED
Summary: ACG detects high osmolality and controls spore dormancy, but the available text does not establish whether this contributes specifically to intracellular water homeostasis.
Reason: A sensor can participate in homeostasis through its signaling output; the old objection that ACG is not itself a water-balance effector was insufficient. The cached paper establishes osmosensing and germination control, but its extracted text lacks the complete results needed to verify the particular water-homeostasis annotation. Preserve the experimental assertion as unresolved rather than reject it by imposing a direct-effector requirement.
Supporting Evidence:
PMID:14718564
Adenylyl cyclase G (ACG) is activated by high osmolality and mediates inhibition of spore germination by this stress factor.
GO:1904360 negative regulation of spore germination
IMP
PMID:14718564
Adenylyl cyclase G is activated by an intramolecular osmosen...
ACCEPT
Summary: ACG activation by high osmolality inhibits spore germination, keeping spores dormant in the fruiting body. This is a core biological role of ACG.
Reason: Loss of ACG abolishes osmotic inhibition of germination, and ACG activation by osmolality mediates this inhibition, directly supporting negative regulation of spore germination.
Supporting Evidence:
PMID:14718564
Adenylyl cyclase G (ACG) is activated by high osmolality and mediates inhibition of spore germination by this stress factor.
GO:0071470 cellular response to osmotic stress
IMP
PMID:8798577
Adenylyl cyclase G, an osmosensor controlling germination of...
ACCEPT
Summary: ACG activity is strongly stimulated by high osmolarity and mediates the cellular response that keeps spores dormant, directly supporting a role in the cellular response to osmotic stress.
Reason: ACG is directly activated by high osmolarity and its disruption removes the osmotic inhibition of germination, supporting this term.
Supporting Evidence:
PMID:8798577
ACG activity, measured in aca-/ACG cells, was strongly stimulated by high osmolarity with optimal stimulation occurring at 200 milliosmolar.
GO:1904360 negative regulation of spore germination
IMP
PMID:8798577
Adenylyl cyclase G, an osmosensor controlling germination of...
ACCEPT
Summary: acg null spores are no longer prevented from germinating by high osmolarity, demonstrating that ACG negatively regulates spore germination.
Reason: The acg- germination phenotype directly establishes ACG as a negative regulator of spore germination under high osmolarity.
Supporting Evidence:
PMID:8798577
acg- cells developed into normal fruiting bodies with viable spores, but spore germination was no longer inhibited by high osmolarity
GO:0004016 adenylate cyclase activity
IDA
PMID:8798577
Adenylyl cyclase G, an osmosensor controlling germination of...
ACCEPT
Summary: Direct measurement of osmolarity-stimulated ACG enzyme activity establishes adenylate cyclase activity as the core catalytic function.
Reason: ACG adenylate cyclase activity was directly assayed and shown to convert ATP to cAMP in an osmolality-dependent manner; this is the core molecular function.
Supporting Evidence:
PMID:8798577
ACG activity, measured in aca-/ACG cells, was strongly stimulated by high osmolarity with optimal stimulation occurring at 200 milliosmolar.
GO:0007231 osmosensory signaling pathway
IMP
PMID:14718564
Adenylyl cyclase G is activated by an intramolecular osmosen...
ACCEPT
Summary: ACG couples direct osmosensing to cAMP production, initiating an osmosensory signaling pathway that controls spore germination. Expression in yeast shows the osmosensor is intrinsic to ACG.
Reason: ACG functions as a primary osmosensor that transduces high osmolality into cAMP signaling, directly supporting participation in an osmosensory signaling pathway.
Supporting Evidence:
PMID:14718564
This strongly suggests that the ACG osmosensor is intramolecular, which would define ACG as the first characterized primary osmosensor in eukaryotes.
GO:0005886 plasma membrane
IDA
PMID:14718564
Adenylyl cyclase G is activated by an intramolecular osmosen...
ACCEPT
Summary: ACG is a transmembrane cyclase active at the plasma membrane, where its extracellular domain and osmosensor face the exterior. Direct localization places ACG at the spore cell periphery.
Reason: As a single-pass type II membrane protein observed at the cell periphery of spores, ACG is active in the plasma membrane.
Supporting Evidence:
PMID:17267449
In spores, ACG was localized at the cell periphery as would be expected for a transmembrane osmosensor
GO:0004016 adenylate cyclase activity
IMP
PMID:14718564
Adenylyl cyclase G is activated by an intramolecular osmosen...
ACCEPT
Summary: Dominant-negative and dimerization experiments confirm ACG cAMP production depends on its catalytic domain and dimerization, consistent with adenylate cyclase activity being the core function.
Reason: ACG cAMP synthesis was measured and shown to require dimerization via a region outside the catalytic domain, supporting its adenylate cyclase activity.
Supporting Evidence:
PMID:14718564
This indicates that ACG activity requires dimerization via a region outside the catalytic domain
GO:0005034 osmosensor activity
IDA
PMID:14718564
Adenylyl cyclase G is activated by an intramolecular osmosen...
ACCEPT
Summary: ACG harbors an intramolecular osmosensor; high osmolality directly activates cAMP synthesis, and this osmosensing is retained when ACG is expressed in a yeast adenylyl cyclase null mutant, showing no auxiliary sensor is required. This is a defining core molecular function.
Reason: Direct evidence establishes ACG as a primary, intramolecular osmosensor, making osmosensor activity a core molecular function.
Supporting Evidence:
PMID:14718564
In yeast, cAMP production by ACG was similarly activated by high osmolality as in Dictyostelium.
PMID:14718564
This strongly suggests that the ACG osmosensor is intramolecular, which would define ACG as the first characterized primary osmosensor in eukaryotes.
GO:0006970 response to osmotic stress
IMP
PMID:14718564
Adenylyl cyclase G is activated by an intramolecular osmosen...
ACCEPT
Summary: ACG mediates the cellular response to high osmolality that inhibits spore germination, supporting a role in response to osmotic stress.
Reason: ACG is directly activated by osmotic up-shift and its loss removes the osmotic block on germination, supporting response to osmotic stress.
Supporting Evidence:
PMID:14718564
Adenylyl cyclase G (ACG) is activated by high osmolality and mediates inhibition of spore germination by this stress factor.
GO:0042802 identical protein binding
IPI
PMID:14718564
Adenylyl cyclase G is activated by an intramolecular osmosen...
KEEP AS NON CORE
Summary: ACG forms homodimers, which is required for its catalytic activity; size fractionation showed dimers between ACG molecules. This self-association is real but is better understood as a structural requirement for the cyclase rather than a standalone function.
Reason: ACG homodimerization is experimentally demonstrated and functionally important for catalysis, but identical protein binding is not itself a core informative molecular function; it underpins the adenylate cyclase activity.
Supporting Evidence:
PMID:14718564
Size fractionation of native ACG showed that dimers were formed between ACG molecules
GO:0010447 response to acidic pH
IDA
PMID:7883072
Regulation of Dictyostelium adenylylcyclases by morphogen-in...
KEEP AS NON CORE
Summary: ACG activity is strongly pH dependent, optimal at pH 8 and virtually absent below pH 7, and is inhibited by weak acids that lower cytosolic pH. This supports a response to acidic pH at the level of enzyme regulation.
Reason: The pH sensitivity of ACG is an experimentally documented regulatory property but is a modulatory response rather than a core evolved function.
Supporting Evidence:
PMID:7883072
basal and GTP gamma S-stimulated ACA activity as well as ACG activity are optimal at pH 8 and are virtually absent below pH 7
GO:0031000 response to caffeine
IDA
PMID:16952277
Pharmacological profiling of the Dictyostelium adenylate cyc...
KEEP AS NON CORE
Summary: Caffeine inhibits cAMP accumulation by ACG (as well as ACA and ACB), documenting a pharmacological response to caffeine.
Reason: Caffeine sensitivity is an experimentally observed pharmacological response, not a physiological core function of ACG.
Supporting Evidence:
PMID:16952277
Caffeine, which was previously used to specifically block ACA function, also inhibited cAMP accumulation by ACB and ACG.
GO:0006970 response to osmotic stress
IEP
PMID:18640994
From drought sensing to developmental control: evolution of ...
ACCEPT
Summary: Across the Dictyostelia, osmolyte-activated ACG activity and osmoregulation of spore germination are conserved, consistent with ACG acting in the response to osmotic stress.
Reason: Comparative and expression evidence supports a conserved role for ACG in osmolality-activated cAMP signaling within the response to osmotic stress.
Supporting Evidence:
PMID:18640994
The osmolyte-activated adenylate cyclase, ACG, produces cAMP for prespore differentiation and inhibition of spore germination.

Core Functions

ACG is an osmolality-activated adenylate cyclase that converts ATP to cAMP at the plasma membrane. High osmolality directly stimulates catalysis, and the resulting intracellular cAMP activates PKA to keep spores dormant and inhibit premature germination.

Supporting Evidence:
  • PMID:8798577
    ACG activity, measured in aca-/ACG cells, was strongly stimulated by high osmolarity with optimal stimulation occurring at 200 milliosmolar.
  • PMID:8798577
    These data indicate that ACG is an osmosensor controlling spore germination through activation of protein kinase A.

ACG functions as a primary, intramolecular osmosensor. Its extracellular/transmembrane region detects high osmolality and directly couples this stimulus to activation of the cytoplasmic cyclase domain, initiating an osmosensory cAMP signaling pathway. This osmosensing is intrinsic to ACG, as it is retained when ACG is expressed in a yeast adenylyl cyclase null mutant.

Molecular Function:
osmosensor activity
Directly Involved In:
Cellular Locations:
Supporting Evidence:
  • PMID:14718564
    This strongly suggests that the ACG osmosensor is intramolecular, which would define ACG as the first characterized primary osmosensor in eukaryotes.
  • PMID:14718564
    In yeast, cAMP production by ACG was similarly activated by high osmolality as in Dictyostelium.

References

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Deep Research

OpenScientist

(acgA-hypotheses/function-hypothesis-go-0001653/openscientist.md)

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πŸ“š Additional Documentation

Notes

(acgA-notes.md)

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