acrA encodes ACR (also called ACB), the terminal-differentiation specific adenylate cyclase of Dictyostelium discoideum. It is a large (2123 aa) multidomain, multi-pass membrane protein comprising seven transmembrane helices, a degenerate histidine kinase region (HisKA plus HATPase-C domains), two receiver (response regulator) domains, and a C-terminal class III nucleotidyl cyclase catalytic domain that converts ATP to 3',5'-cyclic AMP (EC 4.6.1.1), using Mg2+ as cofactor and acting as a homodimer. ACR is expressed at low levels in growing cells and strongly induced during development, peaking during culmination and in prestalk regions of the fruiting body. Unlike the receptor-coupled aggregation adenylate cyclase ACA and the osmosensing spore-dormancy adenylate cyclase ACG, ACR provides the intracellular cAMP that activates cAMP-dependent protein kinase (PKA) at culmination, and is required for spore encapsulation/maturation and for formation of robust (non-thin) stalks. Rather than functioning as a phosphorelay signaling enzyme, its histidine-kinase-like and receiver domains have lost their canonical two-component signaling roles; the dimerizing HisKA subdomain instead serves to promote dimerization of the cyclase domain. Contrary to the plasma-membrane location of ACA, ACR localizes to the endoplasmic reticulum and nuclear envelope. It acts downstream of the cytokinin (discadenine) / DhkB signaling pathway that triggers rapid spore encapsulation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004016 adenylate cyclase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Adenylate cyclase activity is the core, experimentally established molecular function of ACR. The phylogenetic (IBA) inference is fully consistent with direct enzymatic evidence for this protein. Reason: ACR is a bona fide class III adenylate cyclase whose ATP-to-cAMP activity has been directly demonstrated and dissected. This IBA annotation correctly captures the central molecular function. Supporting Evidence: PMID:10556070 we discovered a novel adenylyl cyclase gene, acrA, that is expressed at low levels in growing cells and at more than 25-fold higher levels during development PMID:20966074 In addition to its cyclase (AC) domain, ACR harbors seven transmembrane helices, a histidine kinase domain, and two receiver domains |
| GO:0006171 cAMP biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: ACR synthesizes cAMP, and cAMP biosynthesis is a core biological process for this enzyme, providing the second messenger that activates PKA during terminal differentiation. Reason: The IBA inference of cAMP biosynthesis is directly supported by the catalytic activity of ACR and by the phenotype of acrA null cells, which fail to raise adenylyl cyclase activity after aggregation. Supporting Evidence: PMID:10556070 The increase in activity following aggregation fails to occur in acrA(-) cells PMID:20966074 adenylate cyclase R (ACR), is essential for spore encapsulation |
| GO:0000160 phosphorelay signal transduction system | IEA GO_REF:0000002 | REMOVE | Summary: This InterPro2GO annotation is inferred from the receiver (response-regulator) domain (IPR001789). However, functional dissection of ACR showed that its histidine kinase and receiver domains do NOT act as a phosphorelay to regulate the enzyme; the phosphoryl-accepting aspartates are largely dispensable and the domains have lost the switch-pair residues needed for phosphorylation-induced signaling. Reason: The receiver/histidine-kinase domains are present by ancestry but their canonical phosphorelay function has eroded. Experimental evidence directly contradicts a role for ACR in phosphorelay signal transduction, so this domain-based electronic annotation is an over-annotation. Supporting Evidence: PMID:20966074 indicating that AC activity is not critically regulated by phosphorelay PMID:20966074 This indicates that ACR is not regulated by its intramolecular histidine kinase activity |
| GO:0004016 adenylate cyclase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of adenylate cyclase activity based on RHEA/EC mapping (EC 4.6.1.1). This is correct and redundant with the experimentally supported core molecular function. Reason: The EC/RHEA-based inference matches the directly demonstrated ATP-to-cAMP catalytic activity of ACR. Supporting Evidence: PMID:10556070 we discovered a novel adenylyl cyclase gene, acrA, that is expressed at low levels in growing cells and at more than 25-fold higher levels during development |
| GO:0009190 cyclic nucleotide biosynthetic process | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO annotation from the cyclase domain (IPR001054). It is correct but overly general; ACR specifically synthesizes cAMP, so the more specific child term cAMP biosynthetic process is preferable. Reason: ACR is an adenylate (not general nucleotidyl/guanylyl) cyclase, so the specific term cAMP biosynthetic process better represents its function than the parent cyclic nucleotide biosynthetic process. Proposed replacements: cAMP biosynthetic process Supporting Evidence: PMID:20966074 adenylate cyclase R (ACR), is essential for spore encapsulation |
| GO:0016020 membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: ACR is a multi-pass membrane protein with seven transmembrane helices, so a membrane location is correct. However, the specific experimentally determined locations are the endoplasmic reticulum and nuclear envelope, making the bare membrane term uninformative as a core location. Reason: The generic membrane annotation is technically accurate for this multi-pass membrane protein but is subsumed by the more precise ER and nuclear-envelope localizations shown experimentally. Supporting Evidence: PMID:20966074 This strongly suggests that ACR localizes to the endoplasmic reticulum and nuclear envelope PMID:20966074 In addition to its cyclase (AC) domain, ACR harbors seven transmembrane helices, a histidine kinase domain, and two receiver domains |
| GO:0016772 transferase activity, transferring phosphorus-containing groups | IEA GO_REF:0000002 | REMOVE | Summary: This InterPro2GO annotation derives from the histidine-kinase-like C-terminal (HATPase) domain (IPR004358), implying phosphotransferase activity. But ACR is a lyase (adenylate cyclase, EC 4.6.1.1), and its histidine kinase domain is degenerate and catalytically non-functional, lacking the phospho-accepting histidine, and mutation of essential ATP-binding residues has no effect on activity. Reason: ACR has no demonstrated phosphotransferase/kinase activity; the histidine-kinase-like domain is a pseudokinase used only for dimerization. Assigning transferase activity from this degenerate domain is a domain-based over-annotation contradicted by experimental evidence. Supporting Evidence: PMID:20966074 Mutation of three essential ATP-binding residues in the histidine kinase domain did not affect the AC activity or phenotypic rescue PMID:20966074 the dimerizing histidine phosphoacceptor subdomain, which in ACR lacks the canonical histidine for autophosphorylation, was essential for AC activity |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: ACR produces intracellular cAMP that acts as a second messenger to activate PKA, so participation in intracellular signal transduction is correct. It is a broad process term subsumed by the more specific cAMP biosynthesis and developmental-differentiation annotations. Reason: The annotation is biologically accurate (ACR generates a second-messenger signal) but too general to represent the specific evolved function; retained as non-core context. Supporting Evidence: PMID:10556070 Expression of many of the essential developmental genes in Dictyostelium discoideum are known to depend on PKA activity |
| GO:0009642 response to light intensity | HEP PMID:41057014 Transcriptomic and metabolomic insights into light-mediated ... | KEEP AS NON CORE | Summary: This high-throughput expression (HEP) annotation reflects that acrA is a differentially expressed gene, downregulated in the dark, in a transcriptomic study of light-mediated development. It captures light-regulated expression of acrA rather than a direct functional role of the ACR protein in light responses. Reason: The evidence is transcriptomic/correlative (acrA is a light-responsive DEG). This is peripheral to the core catalytic and developmental function and is retained as non-core. Supporting Evidence: PMID:41057014 Here we also observed that the adenylate cyclase gene acrA was downregulated under dark in the unicellular phase |
| GO:0005524 ATP binding | IC PMID:10556070 An adenylyl cyclase that functions during late development o... | ACCEPT | Summary: ATP binding is curator-inferred (IC) from the adenylate cyclase activity, since ATP is the substrate of the ATP-to-cAMP reaction. This is a correct supporting molecular function. Reason: ATP binding is a necessary component of the cyclase catalytic mechanism (ATP is converted to cAMP plus diphosphate) and is soundly inferred from the enzymatic activity. Supporting Evidence: PMID:10556070 we discovered a novel adenylyl cyclase gene, acrA, that is expressed at low levels in growing cells and at more than 25-fold higher levels during development |
| GO:0004016 adenylate cyclase activity | IDA PMID:10556070 An adenylyl cyclase that functions during late development o... | ACCEPT | Summary: Direct experimental demonstration of adenylate cyclase activity for ACR, the core molecular function. Adenylyl cyclase activity increases through development and this increase is lost in acrA null cells. Reason: This IDA annotation is the primary experimental evidence for the core catalytic function of ACR. Supporting Evidence: PMID:10556070 The increase in activity following aggregation fails to occur in acrA(-) cells |
| GO:0004016 adenylate cyclase activity | IDA PMID:20966074 Functional dissection of adenylate cyclase R, an inducer of ... | ACCEPT | Summary: Direct measurement of cAMP production by an ACR-YFP fusion in acr- cells confirms adenylate cyclase activity and allowed domain-level dissection of the enzyme's catalytic requirements. Reason: Independent IDA evidence for the core adenylate cyclase activity of ACR; the reconstituted enzyme produces cAMP and rescues the null phenotype. Supporting Evidence: PMID:20966074 the dimerizing histidine phosphoacceptor subdomain, which in ACR lacks the canonical histidine for autophosphorylation, was essential for AC activity |
| GO:0005635 nuclear envelope | IDA PMID:20966074 Functional dissection of adenylate cyclase R, an inducer of ... | ACCEPT | Summary: ACR-YFP localizes to the nuclear envelope, shown by confocal microscopy and colocalization with the ER marker calnexin around the nuclei. This is a well-supported, distinctive localization for ACR. Reason: Direct imaging evidence places ACR at the nuclear envelope, an unusual localization for a Dictyostelium adenylate cyclase and a core cellular-component annotation. Supporting Evidence: PMID:20966074 ACR is associated with the nuclear envelope and endoplasmic reticulum PMID:20966074 This strongly suggests that ACR localizes to the endoplasmic reticulum and nuclear envelope |
| GO:0005783 endoplasmic reticulum | IDA PMID:20966074 Functional dissection of adenylate cyclase R, an inducer of ... | ACCEPT | Summary: ACR-YFP colocalizes with the ER marker calnexin in a vesicular network throughout the cell, directly demonstrating endoplasmic reticulum localization. Reason: Direct immunofluorescence/colocalization evidence supports ER localization; this is a core cellular-component annotation for ACR. Supporting Evidence: PMID:20966074 This strongly suggests that ACR localizes to the endoplasmic reticulum and nuclear envelope |
| GO:0030587 sorocarp development | HMP PMID:17659086 High-throughput analysis of spatio-temporal dynamics in Dict... | KEEP AS NON CORE | Summary: High-throughput mutant phenotyping placed acrA among genes whose disruption produces phenotypes only at later (slug-to-culmination) stages of fruiting body (sorocarp) development. This general developmental term is correct but is captured more specifically by the sorocarp morphogenesis and spore-cell differentiation annotations. Reason: The broad sorocarp development term is accurate for acrA but subsumed by more specific late-development annotations that better represent its role. Supporting Evidence: PMID:17659086 In contrast, dhkA and acrA show mutant phenotypes only at later stages consistent with their specific roles during slug to culmination stage |
| GO:0010468 regulation of gene expression | IMP PMID:10556070 An adenylyl cyclase that functions during late development o... | KEEP AS NON CORE | Summary: ACR-derived cAMP activates PKA, and many essential developmental genes depend on PKA activity, so ACR acts upstream of developmental gene expression. This is an indirect, downstream effect mediated by the second-messenger/PKA cascade. Reason: The influence of ACR on gene expression is real but indirect (via cAMP/PKA) and general; it is retained as non-core context rather than a direct molecular function. Supporting Evidence: PMID:10556070 Expression of many of the essential developmental genes in Dictyostelium discoideum are known to depend on PKA activity |
| GO:0031288 sorocarp morphogenesis | IMP PMID:10556070 An adenylyl cyclase that functions during late development o... | ACCEPT | Summary: acrA null cells form unnaturally long, thin stalks, demonstrating a requirement for ACR in proper morphogenesis of the fruiting body (stalk) during culmination. Reason: The stalk-morphogenesis defect of acrA mutants directly supports a core role in sorocarp morphogenesis at culmination. Supporting Evidence: PMID:10556070 Growth and development up to the slug stage are unaffected in acrA(-) mutant strains but the cells make almost no viable spores and produce unnaturally long stalks PMID:10556070 As long as ACA is fully active, ACR is not required until culmination but then plays a critical role in sporulation and construction of the stalk |
| GO:0009736 cytokinin-activated signaling pathway | IMP PMID:18216168 Cytokinins induce sporulation in Dictyostelium. | ACCEPT | Summary: AcrA is required, together with the histidine kinase DhkB, to transduce the cytokinin (discadenine/isopentenyladenine) signal that triggers rapid spore encapsulation. This annotation captures the Dictyostelium cytokinin signaling context in which ACR operates. Reason: Genetic evidence shows AcrA is a required component of the cytokinin signal transduction pathway leading to sporulation, consistent with its role as the cAMP source that activates PKA for encapsulation. Supporting Evidence: PMID:18216168 DhkB and the adenylyl cyclase of late development, AcrA, are members of two component signal transduction families and both are required to transduce the cytokinin signal |
| GO:0031000 response to caffeine | IDA PMID:16952277 Pharmacological profiling of the Dictyostelium adenylate cyc... | KEEP AS NON CORE | Summary: Pharmacological profiling showed that caffeine inhibits cAMP accumulation by ACB (ACR/acrA) in intact cells (an indirect effect, since caffeine does not inhibit basal ACB activity in lysates). This records a response of ACR-dependent cAMP output to caffeine. Reason: The caffeine sensitivity is a pharmacological/experimental property of ACR-dependent cAMP accumulation rather than a core evolved function; retained as non-core. Supporting Evidence: PMID:16952277 Caffeine, which was previously used to specifically block ACA function, also inhibited cAMP accumulation by ACB and ACG |
| GO:0044671 sorocarp spore cell differentiation | IMP PMID:20966074 Functional dissection of adenylate cyclase R, an inducer of ... | ACCEPT | Summary: ACR is essential for spore encapsulation; acr- cells develop to the fruiting body stage but fail to make viable, encapsulated spores, and ACR-YFP rescues this defect. This is a core developmental role of ACR. Reason: Loss- and rescue-of-function evidence establishes ACR as required for spore cell differentiation/encapsulation during culmination. Supporting Evidence: PMID:20966074 adenylate cyclase R (ACR), is essential for spore encapsulation PMID:10556070 As long as ACA is fully active, ACR is not required until culmination but then plays a critical role in sporulation and construction of the stalk |
| GO:0031288 sorocarp morphogenesis | IMP PMID:20966074 Functional dissection of adenylate cyclase R, an inducer of ... | ACCEPT | Summary: A second IMP annotation for sorocarp morphogenesis, from the functional-dissection study in which acr- cells form thinner-than-wild-type stalks that are rescued by ACR-YFP. Reason: Independent genetic evidence confirms a core role for ACR in proper stalk formation during fruiting-body morphogenesis. Supporting Evidence: PMID:20966074 adenylate cyclase R (ACR), is essential for spore encapsulation |
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