sgcA (sGC) is one of the two guanylyl cyclases of Dictyostelium discoideum and provides the great majority of chemoattractant-stimulated cGMP synthesis during cAMP chemotaxis. It is an unusually large (2843 aa, ~315 kDa) cytosolic enzyme whose central pair of class III adenylyl/guanylyl-cyclase catalytic domains is flanked by two large (~1000 aa) N- and C-terminal regions. Despite the "soluble guanylyl cyclase" name it is homologous to mammalian soluble adenylyl cyclase (a class III cyclase) rather than to the metazoan NO-sensitive, heme-containing soluble guanylyl cyclase; its Mg2+/GTP-dependent activity is stimulated by GTPgammaS and inhibited by Ca2+, and there is no evidence for NO or heme regulation. In resting cells the protein is largely cytosolic, and during chemotaxis it translocates to the leading edge, where its N-terminal region binds actin filaments in extending pseudopodia and the enzyme becomes catalytically active upon membrane association. The rapidly diffusing cGMP it produces promotes assembly of myosin II filaments in the cortex and rear of the cell, suppressing lateral pseudopodia and thereby maintaining polarity and directional movement. The sGC protein also has a cGMP-independent activity in which anteriorly localized protein refines and stabilizes pseudopod formation at the leading edge. Loss of the gene reduces chemotactic sensitivity toward cAMP and impairs aggregation, and the protein additionally influences electrotaxis directionality and the timing of intracellular calcium responses.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | IEA GO_REF:0000104 | KEEP AS NON CORE | Summary: sgcA is a class III nucleotide cyclase, and these enzymes use a divalent metal (Mg2+ or Mn2+) for two-metal-ion catalysis. Physiological activity is Mg2+/GTP dependent, so magnesium binding by the catalytic domain is biologically real. This is a cofactor requirement supporting the guanylate cyclase activity rather than a standalone core function. Reason: Magnesium binding is a genuine catalytic cofactor requirement of the cyclase domain (physiological substrate is Mg2+/GTP) but is ancillary to the core guanylate cyclase molecular function. Supporting Evidence: PMID:11500361 prevailing Mg 2+ concentration PMID:11500361 stimulated by GTPΞ³S and inhibited by Ca 2+ ions |
| GO:0006182 cGMP biosynthetic process | IEA GO_REF:0000108 | ACCEPT | Summary: sgcA is the predominant source of chemoattractant-stimulated cGMP in Dictyostelium; gene disruption reduces guanylyl cyclase activity more than 10-fold. The cGMP biosynthetic process annotation is a direct and accurate consequence of the enzyme's guanylate cyclase activity. Reason: cGMP biosynthesis is the core biological output of this guanylate cyclase and is directly supported by experimental gene-disruption data. Supporting Evidence: PMID:11500361 >10-fold reduction in guanylyl cyclase activity |
| GO:0009190 cyclic nucleotide biosynthetic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: This is a correct but more general parent of cGMP biosynthetic process. The specific product of sgcA is cGMP, so the more precise cGMP biosynthetic process term better captures the function. Reason: Accurate but redundant with the more specific cGMP biosynthetic process annotation; retained as a non-core general term. Supporting Evidence: PMID:11500361 >10-fold reduction in guanylyl cyclase activity |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: cGMP produced by sgcA acts as an intracellular second messenger during chemotaxis, so participation in intracellular signal transduction is correct. It is a broad term that does not capture the specific chemotactic role. Reason: Correct high-level process term; retained as non-core because more specific chemotaxis and cGMP-biosynthesis terms better describe the role. Supporting Evidence: PMID:16790492 cGMP plays an important role during chemotaxis |
| GO:0019722 calcium-mediated signaling | IGI PMID:40295210 Intracellular Calcium Responses to External Calcium Stimuli ... | KEEP AS NON CORE | Summary: Genetic analysis shows that gca/sgc-null cells have an altered (slightly delayed) intracellular calcium response to external calcium, and the authors conclude that cGMP participates in calcium homeostasis. This is a modulatory, downstream role rather than a core function of the enzyme. Reason: sgcA/cGMP modulates the timing of calcium responses but this is an accessory role, not the core guanylate-cyclase function. Supporting Evidence: PMID:40295210 gca/sgc-null cells showed a slightly delayed response PMID:40295210 G proteins, cGMP, and IplA are involved in calcium homeostasis |
| GO:0031252 cell leading edge | IDA PMID:19346484 Switching direction in electric-signal-induced cell migratio... | ACCEPT | Summary: In migrating cells the sGC protein localizes to the leading-edge pseudopod in an actin-dependent manner, consistent with direct-imaging data in this and other studies. This is a well-supported localization. Reason: Direct experimental evidence places sGC at the leading-edge pseudopod during directed migration. Supporting Evidence: PMID:19346484 components of the GCase- and PI3K-dependent signaling pathways localized at the leading edge of migrating cells during electrotaxis in an actin-dependent manner |
| GO:0051602 response to electrical stimulus | IGI PMID:19346484 Switching direction in electric-signal-induced cell migratio... | KEEP AS NON CORE | Summary: Genetic modulation of the guanylyl cyclases and the cGMP target GbpC reverses the preferred direction of migration in an electric field (electrotaxis), showing that sgcA acts within the response to an electrical stimulus. This is an accessory role rather than the enzyme's core function. Reason: sgcA contributes to directional switching during electrotaxis, a specialized downstream behavior, not the core molecular function. Supporting Evidence: PMID:19346484 the preferential direction of migration during electrotaxis in Dictyostelium cells can be reversed by genetically modulating both guanylyl cyclases |
| GO:0031252 cell leading edge | IDA PMID:29118357 Pumilio-dependent localization of mRNAs at the cell front co... | ACCEPT | Summary: The four chemotaxis-pathway proteins, including sGC, and their mRNAs are preferentially enriched at the cell front during migration. This supports leading-edge localization of sgcA. Reason: Direct-imaging evidence places sGC among the chemotaxis proteins enriched at the leading edge/cell front. Supporting Evidence: PMID:29118357 proteins of these four chemotaxis pathways and actin are preferentially enriched at the cell front |
| GO:0005829 cytosol | IDA PMID:15601898 Activation of soluble guanylyl cyclase at the leading edge d... | ACCEPT | Summary: In resting cells the major fraction of sGC-GFP is cytosolic, with a small cortical fraction. Cytosolic localization is directly observed and is the resting distribution of the enzyme. Reason: Direct fluorescence imaging shows sGC is predominantly cytosolic in resting cells. Supporting Evidence: PMID:15601898 major fraction of the sGC-GFP fusion protein localizes to the cytosol |
| GO:1904269 cell leading edge cell cortex | IDA PMID:15601898 Activation of soluble guanylyl cyclase at the leading edge d... | ACCEPT | Summary: In a cAMP gradient sGC-GFP relocates to the anterior (leading-edge) cell cortex, where the membrane-associated enzyme is catalytically active. This anterior cortical localization is directly observed. Reason: Direct imaging shows chemoattractant-induced enrichment of sGC at the anterior cell cortex. Supporting Evidence: PMID:15601898 sGC-GFP localizes to the anterior cell cortex |
| GO:0004383 guanylate cyclase activity | IMP PMID:11500361 The Dictyostelium homologue of mammalian soluble adenylyl cy... | ACCEPT | Summary: Gene disruption of sgcA abolishes most guanylyl cyclase activity (>10-fold reduction) without affecting adenylyl cyclase activity, demonstrating that this protein is a guanylate cyclase. This is the core molecular function. Reason: Mutant-phenotype evidence directly establishes guanylate cyclase activity as the core molecular function of sgcA. Supporting Evidence: PMID:11500361 >10-fold reduction in guanylyl cyclase activity |
| GO:0050920 regulation of chemotaxis | IGI PMID:22081140 Dictyostelium chemotaxis: essential Ras activation and acces... | KEEP AS NON CORE | Summary: sGC is one of several accessory signalling enzymes that are not required for basal Ras-driven chemotaxis but provide a memory of direction and improved orientation, amplifying sensitivity in shallow gradients. This is a regulatory contribution to chemotaxis. Reason: Accurate but general regulation-of-chemotaxis role; the specific chemotaxis-to-cAMP annotation better captures the biology. Supporting Evidence: PMID:22081140 they provide a memory of direction and improved orientation of the cell |
| GO:0043327 chemotaxis to cAMP | IGI PMID:18299345 Four key signaling pathways mediating chemotaxis in Dictyost... | ACCEPT | Summary: Genetic screens identify sGC as a key mediator of cAMP chemotaxis. The protein localizes to the leading edge and interacts with actin filaments, while its cGMP product induces myosin filaments in the rear. This directly captures the physiological process sgcA acts within. Reason: sgcA is a central mediator of chemotaxis to cAMP, providing both leading-edge protein and rear cGMP signals. Supporting Evidence: PMID:18299345 this activity is mediated by a soluble guanylyl cyclase PMID:18299345 cyclic guanosine monophosphate product induces myosin filaments in the rear of the cell |
| GO:0006935 chemotaxis | IGI PMID:18073238 The role of cGMP and the rear of the cell in Dictyostelium c... | KEEP AS NON CORE | Summary: sGC/cGMP contributes to chemotaxis by maintaining a quiescent rear and efficient pseudopod retraction, which increases directional movement and stable cell streaming. This is a correct but general parent of the more specific chemotaxis-to-cAMP annotation. Reason: Correct but broad; the specific chemotaxis-to-cAMP term is the more informative core process annotation. Supporting Evidence: PMID:18073238 quiescent rear of the cell increases the efficiency of directional movement |
| GO:0120320 lateral pseudopodium retraction | IGI PMID:18073238 The role of cGMP and the rear of the cell in Dictyostelium c... | KEEP AS NON CORE | Summary: cGMP produced by sGC promotes cortical myosin in the rear, enabling efficient retraction of lateral/rear pseudopodia during the rising flank of the cAMP wave. sgcA acts within this process. Reason: A specific downstream consequence of cGMP/myosin signalling; accurate but not the core molecular function. Supporting Evidence: PMID:18073238 efficiently retract pseudopodia in the rear of the cell during the rising flank of the cAMP wave |
| GO:0004383 guanylate cyclase activity | IDA PMID:16790492 Guanylyl cyclase protein and cGMP product independently cont... | ACCEPT | Summary: The sGC protein is the predominant guanylyl cyclase producing cGMP during chemotaxis; a point mutation in the catalytic site (sGCDeltacat) abolishes activity, confirming direct guanylate cyclase function. Core molecular function. Reason: Direct experimental evidence, including a catalytically dead point mutant, establishes guanylate cyclase activity as the core function. Supporting Evidence: PMID:16790492 cGMP plays an important role during chemotaxis and is produced predominantly by a soluble guanylyl cyclase |
| GO:0006935 chemotaxis | IMP PMID:16790492 Guanylyl cyclase protein and cGMP product independently cont... | KEEP AS NON CORE | Summary: gc-null cells have a reduced chemotaxis index (0.43 vs 0.64 for cells expressing wild-type sGC), demonstrating that sgcA is required for full chemotactic efficiency. Correct but general process term. Reason: Mutant-phenotype support for a general chemotaxis role; the specific chemotaxis-to-cAMP term better captures the core process. Supporting Evidence: PMID:16790492 chemotaxis index of gc -null cells of 0.43 |
| GO:0015629 actin cytoskeleton | IDA PMID:16790492 Guanylyl cyclase protein and cGMP product independently cont... | ACCEPT | Summary: The sGC protein associates with actin filaments in pseudopodia via its N-terminal region; this actin association targets the enzyme to the leading edge and underlies its cGMP-independent role in refining pseudopod formation. A directly observed and functionally important localization. Reason: Direct evidence that sGC colocalizes with/associates with the actin cytoskeleton in pseudopodia, a key aspect of its leading-edge behavior. Supporting Evidence: PMID:16790492 sGC protein associates with actin filaments in pseudopodia |
| GO:0031033 myosin filament organization | IGI PMID:16790492 Guanylyl cyclase protein and cGMP product independently cont... | KEEP AS NON CORE | Summary: cGMP from sGC drives incorporation of myosin into the cell cortex; cGMP-null cells incorporate almost no myosin in the posterior cortex during chemotaxis. sgcA acts upstream of cortical myosin filament organization. Reason: Genuine downstream effect of cGMP signalling on cortical myosin, but an accessory process rather than the core molecular function. Supporting Evidence: PMID:16790492 incorporate almost no myosin in the posterior cell cortex during chemotaxis |
| GO:0031252 cell leading edge | IDA PMID:16790492 Guanylyl cyclase protein and cGMP product independently cont... | ACCEPT | Summary: The sGC protein is enriched in extending pseudopodia at the leading edge during chemotaxis. This is directly observed and is a core aspect of the enzyme's spatial behavior. Reason: Direct imaging shows sGC enrichment at the leading edge during chemotaxis. Supporting Evidence: PMID:16790492 The sGC protein is enriched in extending pseudopodia at the leading edge of the cell during chemotaxis |
| GO:0031037 myosin II filament disassembly | TAS PMID:14710184 Chemotaxis: signalling modules join hands at front and tail. | KEEP AS NON CORE | Summary: This review describes the cGMP cascade as regulating myosin filament formation in the posterior of the cell to inhibit lateral pseudopodia. Because the cascade primarily promotes cortical myosin II assembly, the disassembly direction is debatable; the annotation nonetheless correctly places sgcA within myosin II filament turnover, a downstream process. Reason: TAS from a secondary review; sgcA/cGMP acts within cortical myosin II filament dynamics (the cascade chiefly promotes filament formation), an accessory role rather than the core function. Supporting Evidence: PMID:14710184 regulates myosin filament formation in the posterior of the cell |
| GO:0120320 lateral pseudopodium retraction | TAS PMID:14710184 Chemotaxis: signalling modules join hands at front and tail. | KEEP AS NON CORE | Summary: The cGMP-signalling cascade regulates posterior myosin filament formation and thereby inhibits the formation of lateral pseudopodia that would misdirect the cell. sgcA acts within this process. Reason: Accurate downstream role in suppressing lateral pseudopodia via cGMP; accessory to the core guanylate cyclase function. Supporting Evidence: PMID:14710184 inhibiting the formation of lateral pseudopodia |
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