SCG5

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0030234 enzyme regulator activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation to enzyme regulator activity is well supported. SCG5/7B2 has dual enzyme-regulatory functions towards PCSK2/PC2. The N-terminal domain facilitates proPC2 transport and activation (acting as an enzyme activator), while the C-terminal peptide acts as a specific inhibitor of PC2 enzymatic activity (PMID:9348280, PMID:11439082). GO:0030234 (enzyme regulator activity) appropriately captures this dual regulatory role at the right level of specificity given that 7B2 both activates and inhibits the same enzyme at different stages. The IBA evidence is phylogenetically well-supported. Reason: The IBA annotation to enzyme regulator activity accurately captures the core molecular function of SCG5/7B2 as a regulator of PC2. This is the appropriate parent term given that 7B2 has both activating and inhibiting activities toward the same enzyme. Supporting Evidence: PMID:9348280 7B2 acts as a helper protein involved in proPC2 transport and is required in the proPC2 activation process PMID:11439082 Its C-terminal peptide can inhibit PC2 in vitro and may contribute to keep the enzyme transiently inactive in vivo
GO:0046883 regulation of hormone secretion	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation to regulation of hormone secretion is supported by evidence that 7B2-null mice develop Cushing's disease due to ACTH hypersecretion from the neurointermediate lobe (PMID:11439082), indicating that 7B2 plays a role in regulating hormone secretion. The UniProt function annotation also states that 7B2 plays a role in regulating pituitary hormone secretion. However, this is a secondary consequence of 7B2's primary function as a PC2 regulator -- loss of 7B2 leads to loss of PC2 activity, which disrupts prohormone processing and consequently affects hormone secretion. This represents a downstream biological process rather than a direct core molecular function. Reason: While regulation of hormone secretion is a genuine biological role of SCG5/7B2, it is a downstream consequence of its primary function as a PC2 regulator and transporter. The 7B2-null mouse phenotype (Cushing's disease, ACTH hypersecretion) demonstrates this role, but it is indirect -- arising from failed PC2 activation and consequent impaired prohormone processing. Supporting Evidence: PMID:11439082 unlike PC2-null mice, which are viable, 7B2-null mutants die early in life from Cushing's disease due to corticotropin ('ACTH') hypersecretion by the neurointermediate lobe, suggesting a possible involvement of 7B2 in secretory granule formation and in secretion regulation
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation to extracellular region is derived from UniProtKB subcellular location mapping. UniProt annotates SCG5/7B2 as Secreted (ECO:0000250, by similarity with UniProtKB:P01165, the Xenopus ortholog). 7B2 is a secretory protein that is released from neuroendocrine cells via the regulated secretory pathway. It resides in secretory granules and is ultimately secreted. The annotation to extracellular region is correct but quite broad; the protein is found extracellularly after regulated secretion. Reason: SCG5/7B2 is a secreted neuroendocrine protein that is released from secretory granules. The IEA annotation to extracellular region is consistent with UniProt subcellular localization data and with the known biology of 7B2 as a protein of the regulated secretory pathway that is ultimately released extracellularly. Supporting Evidence: PMID:11439082 7B2 is an acidic protein residing in the secretory granules of neuroendocrine cells
GO:0007218 neuropeptide signaling pathway	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: IEA annotation to neuropeptide signaling pathway is based on InterPro and UniProtKB keyword mapping. While SCG5/7B2 is classified as a neuropeptide (UniProt KW-0527), its primary function is as a regulator of PC2 rather than as a signaling neuropeptide per se. 7B2 is processed in the secretory pathway and its peptide products are released, but its known biological role is regulating PC2 maturation and activity, not acting as a signaling ligand. The annotation to neuropeptide signaling pathway overstates the direct role of 7B2 in signaling. There is no evidence that 7B2 or its derived peptides act as receptor ligands in a neuropeptide signaling pathway. Reason: While SCG5/7B2 is classified as a neuropeptide and is present in neuroendocrine cells, there is no evidence that it directly participates in neuropeptide signaling as a signaling molecule (i.e., as a ligand for a receptor). Its function is as a PC2 chaperone/regulator in the secretory pathway. The IEA mapping from the neuropeptide keyword is too liberal. Supporting Evidence: PMID:11439082 In neuroendocrine cells, 7B2 functions as a specific chaperone for the proprotein convertase (PC) 2
GO:0030141 secretory granule	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation to secretory granule is based on InterPro domain mapping (IPR007945, Secretogranin_V). SCG5/7B2 is well established as a resident of neuroendocrine secretory granules. The UniProt subcellular location note states that 7B2 resides in neuroendocrine and endocrine secretory granules. The 1988 cloning paper (PMID:3134253) described 7B2 as a protein sorted to secretory granules. This is a well-supported cellular component annotation. Reason: Localization of SCG5/7B2 to secretory granules is well established and is consistent with its known biology as a neuroendocrine secretory pathway protein. Supporting Evidence: PMID:3134253 This protein of unknown function, which is sorted to secretory granules, appears to be present selectively in neurons and endocrine cells PMID:11439082 7B2 is an acidic protein residing in the secretory granules of neuroendocrine cells
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: IPI annotation to protein binding based on high-throughput proteome-scale interactome mapping (PMID:25416956, Rolland et al. 2014). The with/from field indicates interaction with UBQLN1 (Q9UMX0). UBQLN1 (ubiquilin-1) is involved in proteasomal degradation and ER-associated degradation. While the interaction is derived from a systematic yeast two-hybrid screen, the biological relevance of SCG5 interacting with UBQLN1 is unclear. The protein binding term is uninformative and does not tell us about the actual molecular function of SCG5. Reason: Protein binding (GO:0005515) is uninformative and does not capture any specific molecular function. This is a high-throughput interaction with UBQLN1 from a proteome-scale screen (PMID:25416956). The biological significance of the SCG5-UBQLN1 interaction is not established and does not illuminate the core function of SCG5. Per curation guidelines, generic protein binding annotations should be avoided in favor of more informative terms.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: IPI annotation to protein binding based on the reference map of the human binary protein interactome (PMID:32296183, Luck et al. 2020). The with/from fields indicate interactions with MEOX2 (Q6FHY5) and UBQLN2 (Q9UHD9). MEOX2 is a homeobox transcription factor, and UBQLN2 is related to UBQLN1 in proteasomal degradation. These are from high-throughput binary interaction screens. The biological relevance of these interactions for SCG5 function is unclear. Protein binding is uninformative. Reason: Protein binding (GO:0005515) is uninformative. These high-throughput interactions from a proteome-scale binary interactome map (PMID:32296183) with MEOX2 and UBQLN2 have no established biological significance for SCG5 function. Per curation guidelines, generic protein binding annotations should be avoided.
GO:0004857 enzyme inhibitor activity	IEA GO_REF:0000107	MODIFY	Summary: IEA annotation to enzyme inhibitor activity transferred from mouse ortholog (UniProtKB:P12961) via Ensembl Compara. The C-terminal peptide of 7B2 is a well-established specific inhibitor of PC2 enzymatic activity (PMID:9348280, PMID:11439082). This function has been demonstrated in vitro and the CT peptide constitutes a potent and specific inhibitor of PC2. The MEROPS database classifies SCG5 as I21.001. The annotation is correct but could be made more specific -- the inhibited enzyme (PC2) is a serine-type endopeptidase (subtilisin family), so GO:0004867 (serine-type endopeptidase inhibitor activity) would be a more precise term. Reason: The annotation to enzyme inhibitor activity is correct in substance but too general. PC2/PCSK2 is a subtilisin-like serine endopeptidase, and the 7B2 C-terminal peptide is a specific inhibitor of this enzyme. A more informative annotation would be to GO:0004867 (serine-type endopeptidase inhibitor activity). Proposed replacements: serine-type endopeptidase inhibitor activity Supporting Evidence: PMID:9348280 The identity of this activity as PC2 was demonstrated by its complete inhibition by the 7B2 CT peptide PMID:11439082 Its C-terminal peptide can inhibit PC2 in vitro and may contribute to keep the enzyme transiently inactive in vivo
GO:0005634 nucleus	IEA GO_REF:0000107	REMOVE	Summary: IEA annotation to nucleus transferred from mouse ortholog via Ensembl Compara. SCG5/7B2 is a secretory pathway protein with a signal peptide that directs it to the ER. It is well established as a secretory granule resident protein that is ultimately secreted. The UniProt entry does not annotate nuclear localization for human SCG5 -- it lists only Secreted as the subcellular location. There is no evidence in the primary literature (PMID:7913882, PMID:9348280, PMID:11439082) supporting nuclear localization of 7B2. This appears to be an erroneous transfer from the mouse ortholog that may itself have been incorrectly annotated. Reason: There is no evidence supporting nuclear localization of SCG5/7B2. The protein has a signal peptide, is routed through the secretory pathway (ER to Golgi to secretory granules), and is ultimately secreted. UniProt annotates it only as Secreted. Nuclear localization is inconsistent with the known biology of this protein. The IEA transfer from the mouse ortholog is likely erroneous. Supporting Evidence: PMID:11439082 7B2 is an acidic protein residing in the secretory granules of neuroendocrine cells PMID:7913882 the precursor form of 7B2 interacts with the proform of PC2. Pulse-chase analysis revealed that this association is transient in that it commences early in the secretory pathway, while dissociation in the later stages appears to coincide with the cleavages of 7B2, proPC2, and prohormone
GO:0006886 intracellular protein transport	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation to intracellular protein transport transferred from mouse ortholog via Ensembl Compara. SCG5/7B2 facilitates the transport of proPC2 from the ER to the Golgi. Muller et al. 1997 (PMID:9348280) demonstrated that 7B2 increases proPC2 transport to the Golgi by stabilizing a transport-competent conformation. This is a core function of 7B2 and the annotation is well supported. Reason: Intracellular protein transport is a well-established function of SCG5/7B2. The protein binds folded proPC2 in the ER and facilitates its transport to the Golgi and later secretory compartments. This is one of the core biological processes in which 7B2 participates. Supporting Evidence: PMID:9348280 Under experimental conditions that prevent propeptide cleavage, 7B2 expression increased proPC2 transport to the Golgi PMID:9348280 we propose that 7B2 stabilizes a transport-competent conformation of proPC2. This stabilization results in an increase in transport to the Golgi
GO:0016486 peptide hormone processing	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation to peptide hormone processing transferred from mouse ortholog via Ensembl Compara. SCG5/7B2 is required for proper activation of PC2, which is itself a key enzyme in peptide hormone processing. By enabling PC2 to achieve its active form, 7B2 indirectly contributes to peptide hormone processing. However, 7B2 does not itself directly process peptide hormones -- it regulates the enzyme (PC2) that does. This is a secondary downstream consequence of 7B2's primary role as a PC2 regulator. Reason: SCG5/7B2 indirectly contributes to peptide hormone processing by enabling PC2 activation, but it does not directly process peptide hormones. The annotation is not wrong but represents an indirect role downstream of the core function as a PC2 regulator and transporter. Supporting Evidence: PMID:9348280 7B2 is required for the productive cleavage of the propeptide, i.e., for the generation of active mature PC2 PMID:11439082 The PC2-7B2 model defines a new neuroendocrine paradigm whereby proteolytic activation of prohormones and proneuropeptides in the secretory pathway is spatially and temporally regulated by the dynamics of interactions between converting enzymes and their binding proteins
GO:0046883 regulation of hormone secretion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation to regulation of hormone secretion transferred from mouse ortholog via Ensembl Compara. This duplicates the IBA annotation (GO_REF:0000033) for the same GO term. The evidence is the same as discussed for the IBA entry above -- 7B2 indirectly regulates hormone secretion through its role as a PC2 regulator. The IBA evidence is more authoritative. Reason: Duplicate of the IBA annotation to GO:0046883. The IEA transfer is consistent with the IBA annotation. This is a secondary downstream role. Supporting Evidence: PMID:11439082 7B2-null mutants die early in life from Cushing's disease due to corticotropin ('ACTH') hypersecretion by the neurointermediate lobe
GO:0004857 enzyme inhibitor activity	ISS GO_REF:0000024	MODIFY	Summary: ISS annotation to enzyme inhibitor activity transferred manually from mouse ortholog (UniProtKB:P12961). The C-terminal peptide of 7B2 is a well-characterized specific inhibitor of PC2 activity (PMID:9348280, PMID:11439082). As with the IEA annotation, this is correct in substance but could be more specific. PC2 is a subtilisin-like serine endopeptidase, so GO:0004867 (serine-type endopeptidase inhibitor activity) would be more informative. Reason: Same rationale as for the IEA annotation to GO:0004857. The term is correct but too general. GO:0004867 (serine-type endopeptidase inhibitor activity) would more precisely capture the function of the 7B2 CT peptide as an inhibitor of PC2, which is a subtilisin-like serine endopeptidase. Proposed replacements: serine-type endopeptidase inhibitor activity Supporting Evidence: PMID:9348280 The identity of this activity as PC2 was demonstrated by its complete inhibition by the 7B2 CT peptide PMID:11439082 Its C-terminal peptide can inhibit PC2 in vitro and may contribute to keep the enzyme transiently inactive in vivo
GO:0006886 intracellular protein transport	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation to intracellular protein transport transferred manually from mouse ortholog (UniProtKB:P12961). This duplicates the IEA annotation for the same GO term. 7B2 facilitates proPC2 transport from the ER to the Golgi as demonstrated in PMID:9348280. The annotation is well supported. Reason: Intracellular protein transport is a core biological process for SCG5/7B2. Duplicate of the IEA annotation but with ISS evidence from manual curation, which is appropriate. Supporting Evidence: PMID:9348280 Under experimental conditions that prevent propeptide cleavage, 7B2 expression increased proPC2 transport to the Golgi
GO:0016486 peptide hormone processing	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation to peptide hormone processing transferred manually from mouse ortholog (UniProtKB:P12961). Same assessment as the IEA annotation -- 7B2 indirectly contributes to peptide hormone processing by enabling PC2 activation, but does not directly process peptide hormones. Reason: Same rationale as the IEA annotation. Indirect contribution to peptide hormone processing through enabling PC2 activation. Supporting Evidence: PMID:9348280 7B2 is required for the productive cleavage of the propeptide, i.e., for the generation of active mature PC2
GO:0030141 secretory granule	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation to secretory granule transferred manually from Xenopus ortholog (UniProtKB:P01165). 7B2 is well established as a secretory granule resident protein. This duplicates the IEA annotation for the same GO term and is well supported. Reason: Localization to secretory granules is well established for SCG5/7B2 and is consistent with its known biology. The ISS evidence from the Xenopus ortholog is appropriate. Supporting Evidence: PMID:3134253 This protein of unknown function, which is sorted to secretory granules, appears to be present selectively in neurons and endocrine cells PMID:11439082 7B2 is an acidic protein residing in the secretory granules of neuroendocrine cells
GO:0046883 regulation of hormone secretion	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation to regulation of hormone secretion transferred manually from mouse ortholog (UniProtKB:P12961). This is a third annotation to the same GO term (also annotated by IBA and IEA). Same assessment applies -- this is a secondary downstream role of 7B2. Reason: Same rationale as the IBA and IEA annotations. Regulation of hormone secretion is an indirect consequence of 7B2's primary role as a PC2 regulator. Supporting Evidence: PMID:11439082 7B2-null mutants die early in life from Cushing's disease due to corticotropin ('ACTH') hypersecretion by the neurointermediate lobe
GO:0051082 unfolded protein binding	IDA PMID:7913882 7B2 is a neuroendocrine chaperone that transiently interacts...	MODIFY	Summary: GO:0051082 is now formally obsolete (go-ontology#30962). The original annotation was based on Braks and Martens 1994 (PMID:7913882), which described 7B2 as a neuroendocrine chaperone for proPC2. While the paper showed that 7B2 has distant sequence similarity to chaperonins and specifically associates with proPC2, a follow-up study by Braks and Martens 1997 (PMID:9348280) explicitly demonstrated that 7B2 is NOT involved in PC2 folding. That study showed proPC2 must fold before binding 7B2, and that 7B2 functions as a transport facilitator and activation cofactor rather than a folding chaperone. The UniProt function annotation for SCG5 (P05408) also states that 7B2 is required for cleavage of PCSK2 but does not appear to be involved in its folding. Therefore, the annotation to unfolded protein binding is incorrect on two counts -- (1) 7B2 does not bind unfolded proteins generally, it specifically binds folded proPC2, and (2) it does not assist in protein folding. GO:0044183 (protein folding chaperone) is also not appropriate because 7B2 does not assist in the folding process. The most accurate replacement term is GO:0140318 (protein transporter activity), which describes directly binding to a specific protein and delivering it to a specific cellular location, consistent with 7B2 escorting proPC2 from the ER to later secretory compartments. The existing annotations to enzyme inhibitor activity (GO:0004857) and enzyme regulator activity (GO:0030234) already capture the other core molecular functions of 7B2. Reason: The annotation to GO:0051082 (unfolded protein binding) is incorrect for SCG5/7B2. The term is now formally obsolete (go-ontology#30962). Furthermore, the evidence does not support unfolded protein binding for 7B2. Braks and Martens 1997 (PMID:9348280) conclusively demonstrated that proPC2 must fold before binding 7B2, and that 7B2 is involved in proPC2 transport and activation but not folding. GO:0044183 (protein folding chaperone) is also inappropriate because 7B2 does not assist in the protein folding process. The best replacement is GO:0140318 (protein transporter activity), defined as directly binding to a specific protein and delivering it to a specific cellular location, which accurately describes 7B2 escorting folded proPC2 from the ER through the secretory pathway. Proposed replacements: protein transporter activity Supporting Evidence: PMID:7913882 the amino-terminal half of 7B2 is distantly related to chaperonins, a subclass of molecular chaperones. When incubated in vitro with newly synthesized pituitary proteins, recombinant 7B2 specifically associates with prohormone convertase PC2...this association is transient in that it commences early in the secretory pathway, while dissociation in the later stages appears to coincide with the cleavages of 7B2, proPC2, and prohormone PMID:9348280 7B2 is not involved in the early steps of proPC2 folding, and that proPC2 must fold before binding 7B2 PMID:9348280 rather than promoting proPC2 folding, 7B2 acts as a helper protein involved in proPC2 transport and is required in the proPC2 activation process
GO:0005515 protein binding	IPI PMID:7913882 7B2 is a neuroendocrine chaperone that transiently interacts...	MARK AS OVER ANNOTATED	Summary: IPI annotation to protein binding based on coimmunoprecipitation of 7B2 with PCSK2/proPC2 (PMID:7913882, Braks and Martens 1994). The with/from indicates interaction with UniProtKB:P16519 (PCSK2). This interaction is the cornerstone of SCG5/7B2 function -- the specific binding to proPC2 that enables transport and activation. However, protein binding (GO:0005515) is uninformative. The actual molecular function is better captured by the existing annotations to enzyme regulator activity (GO:0030234), enzyme inhibitor activity (GO:0004857), protein transporter activity (GO:0140318, proposed replacement for GO:0051082), and enzyme activator activity (GO:0008047). Reason: While the interaction between SCG5/7B2 and PCSK2/proPC2 is biologically real and critical, protein binding (GO:0005515) is uninformative per curation guidelines. The functional significance of this interaction is already captured by the more specific annotations to enzyme regulator activity, enzyme inhibitor activity, and the proposed protein transporter activity. Supporting Evidence: PMID:7913882 recombinant 7B2 specifically associates with prohormone convertase PC2 PMID:7913882 the precursor form of 7B2 interacts with the proform of PC2
GO:0005525 GTP binding	TAS PMID:3134253 Cloning and sequence analysis of human pituitary cDNA encodi...	REMOVE	Summary: TAS annotation to GTP binding based on the original cloning paper by Martens 1988 (PMID:3134253). That paper identified three regions in the 7B2 sequence that were homologous to GTP-binding domains, stating that 7B2 had structural characteristics of a GTP-binding protein. However, this was purely a sequence analysis observation from the early characterization of 7B2 and was never experimentally confirmed. No subsequent study has demonstrated that 7B2 actually binds GTP. The comprehensive 2001 review by Mbikay et al. (PMID:11439082) does not mention GTP binding as a function of 7B2. All subsequent functional characterization has focused on the PC2 chaperone/regulator role. The initial sequence homology observation was likely a spurious match that has not been substantiated. Reason: The GTP binding annotation is based solely on a weak sequence homology observation from the 1988 cloning paper (PMID:3134253) that identified regions with similarity to GTP-binding domains. This was never experimentally validated. No subsequent study over more than 35 years has confirmed GTP binding activity for 7B2. The comprehensive review (PMID:11439082) does not mention GTP binding. The TAS evidence code is inappropriate here as the cited paper only noted sequence similarity, not actual GTP binding activity. This annotation should be removed as unsupported. Supporting Evidence: PMID:3134253 the presence of three regions homologous to GTP-binding domains giving 7B2 structural characteristics of a GTP-binding protein
GO:0008047 enzyme activator activity	ISS PMID:9348280 Mechanism of the facilitation of PC2 maturation by 7B2 invol...	NEW	Summary: 7B2 is required for the productive activation of proPC2 into active mature PC2. Muller et al. 1997 (PMID:9348280) demonstrated that in vitro, 7B2 was required for proPC2 activation at acidic pH, and that without 7B2, proPC2 propeptide cleavage results in the formation of inactive enzyme. The review by Mbikay et al. 2001 (PMID:11439082) confirms that 7B2 facilitates proPC2 transport and activation. This enzyme activator function is distinct from and complementary to the enzyme inhibitor function of the CT peptide. The existing annotation to enzyme regulator activity (GO:0030234) covers both roles, but enzyme activator activity (GO:0008047) specifically captures the activation function of the N-terminal domain. Reason: SCG5/7B2 functions as a specific activator of PC2. It is required for the productive activation of proPC2 -- without 7B2, propeptide cleavage produces inactive enzyme. This is a core molecular function that should be explicitly annotated in addition to the broader enzyme regulator activity and the enzyme inhibitor activity of the CT peptide. Supporting Evidence: PMID:9348280 In vitro, 7B2 was required for proPC2 activation at an acidic pH PMID:9348280 whereas the PC2 propeptide can be cleaved from proPC2 in the absence of 7B2, this cleavage only results in the formation of inactive enzyme. These data support a direct link between 7B2 and proPC2 activation PMID:11439082 it binds to an inactive proPC2 and facilitates its transport from the endoplasmic reticulum to later compartments of the secretory pathway where the zymogen is proteolytically matured and activated

Gene Description

Existing Annotations Review

Core Functions

The N-terminal domain of SCG5/7B2 acts as a specific enzyme activator for PC2, required for the productive proteolytic maturation of proPC2 into active enzyme.

The C-terminal peptide of SCG5/7B2 functions as a potent and specific inhibitor of PC2 enzymatic activity, preventing premature activation of the enzyme in early secretory compartments.

References

Deep Research

Falcon

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