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 being obsoleted (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 being obsoleted (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

Core Functions

SCG5/7B2 functions as a specific molecular chaperone/transporter for proprotein convertase 2 (PCSK2/PC2). The N-terminal domain binds folded proPC2 in the ER and facilitates its transport through the secretory pathway to compartments where PC2 is proteolytically matured and activated. Without 7B2, proPC2 propeptide cleavage produces inactive enzyme. 7B2 is required for productive PC2 activation. Full-length 7B2 (~27 kDa) is cleaved by Golgi-resident furin to yield a ~21 kDa product, and both forms contain a central intrinsically disordered region (IDR) that influences client binding and oligomerization (DOI:10.3389/fnagi.2020.00268). In human islets, the major physiological PC2/7B2-dependent processing step is proglucagon-to-glucagon in alpha-cells rather than beta-cell proinsulin maturation (DOI:10.2337/db19-0276). Beyond PC2, 7B2 also suppresses aggregation of amyloidogenic peptides including beta-amyloid, alpha-synuclein, and IAPP, consistent with a broader secreted chaperone role in extracellular proteostasis (DOI:10.3389/fnagi.2020.00268, DOI:10.2337/db19-0276).

Molecular Function:

protein transporter activity

Directly Involved In:

intracellular protein transport

Cellular Locations:

endoplasmic reticulum lumen secretory granule

Supporting Evidence:

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
PMID:9348280
Under experimental conditions that prevent propeptide cleavage, 7B2 expression increased proPC2 transport to the Golgi

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.

Molecular Function:

enzyme activator activity

Directly Involved In:

intracellular protein transport

Cellular Locations:

secretory granule

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

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.

Molecular Function:

serine-type endopeptidase inhibitor activity

Cellular Locations:

secretory granule

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

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:3134253

Cloning and sequence analysis of human pituitary cDNA encoding the novel polypeptide 7B2.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:7913882

7B2 is a neuroendocrine chaperone that transiently interacts with prohormone convertase PC2 in the secretory pathway.

PMID:9348280

Mechanism of the facilitation of PC2 maturation by 7B2 involvement in ProPC2 transport and activation but not folding.

PMID:11439082

Neuroendocrine secretory protein 7B2 structure, expression and functions.

DOI:10.3389/fnagi.2020.00268

Secreted Chaperones in Neurodegeneration

7B2 is a neuroendocrine secreted chaperone protein packaged with neuropeptides and released during synaptic activity, with client binding influenced by its intrinsically disordered region and oligomerization behavior.
Full-length 7B2 (~27 kDa) is cleaved by the Golgi-resident convertase furin to yield a ~21 kDa product; both forms contain a central intrinsically disordered region (IDR).
CSF levels of 7B2 are approximately 3 ng/mL (0.14 nM) and decline with age, and SCG5 has been recurrently identified in AD vs control CSF proteomics studies.

DOI:10.2337/db19-0276

Revisiting Proinsulin Processing -- Evidence That Human Beta-Cells Process Proinsulin With Prohormone Convertase (PC) 1/3 but Not PC2

In human islets, PC2 immunoreactivity is primarily in alpha-cells and nearly undetectable in beta-cells, contrasting with mouse islets where both cell types express PC2.
PC2 inhibition nearly blocks glucagon production but does not significantly change proinsulin processing in pulse-chase experiments on human islets.
7B2 immunoreactivity is detectable in both alpha- and beta-cells in human islets, but the intensity is lower in beta-cells than alpha-cells.
Prior reports indicate that 7B2 suppresses aggregation and cytotoxicity for amyloidogenic peptides including beta-amyloid, synuclein, and IAPP.

DOI:10.1101/2023.01.18.523916

Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric Abeta

SCG5 is among proteins with reported chaperone activity whose secretion is altered in astrocytes exposed to Abeta oligomer-containing medium.
SCG5 has been identified in 4 of 10 AD vs control CSF proteomics studies reviewed, and chromogranins/secretogranins are proposed AD biomarkers with decreased CSF levels.

DOI:10.1038/s41598-024-76722-1

Cystic fibrosis-related diabetes is associated with reduced islet protein expression of GLP-1 receptor and perturbation of cell-specific transcriptional programs

Spatial transcriptomics of human pancreas in CFRD reveals SCG5 downregulation in both alpha- and beta-cells, with the authors connecting SCG5/7B2 to its known PC2 chaperone role and hypothesizing that reduced SCG5 could impair proglucagon-to-glucagon processing and IAPP processing.

📚 Additional Documentation

Deep Research Falcon

(SCG5-deep-research-falcon.md)

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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P05408
Protein Description: RecName: Full=Neuroendocrine protein 7B2; AltName: Full=Pituitary polypeptide; AltName: Full=Secretogranin V; AltName: Full=Secretogranin-5; AltName: Full=Secretory granule endocrine protein I; Contains: RecName: Full=N-terminal peptide; Contains: RecName: Full=C-terminal peptide; Flags: Precursor;
Gene Information: Name=SCG5; Synonyms=SGNE1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the 7B2 family. .
Key Domains: Secretogranin_V. (IPR007945); Secretogranin_V (PF05281)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SCG5" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'SCG5' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene SCG5 (gene ID: SCG5, UniProt: P05408) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P05408
Protein Description: RecName: Full=Neuroendocrine protein 7B2; AltName: Full=Pituitary polypeptide; AltName: Full=Secretogranin V; AltName: Full=Secretogranin-5; AltName: Full=Secretory granule endocrine protein I; Contains: RecName: Full=N-terminal peptide; Contains: RecName: Full=C-terminal peptide; Flags: Precursor;
Gene Information: Name=SCG5; Synonyms=SGNE1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the 7B2 family. .
Key Domains: Secretogranin_V. (IPR007945); Secretogranin_V (PF05281)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SCG5" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene SCG5 (gene ID: SCG5, UniProt: P05408) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Gene functional annotation research report: Human SCG5 (UniProt P05408; neuroendocrine protein 7B2 / secretogranin V)

Target verification (critical identity check)

The target protein is human neuroendocrine protein 7B2, encoded by SCG5 (also referred to as secretogranin V/secretogranin-5), and is described in the literature explicitly as the “essential PC2 cofactor neuroendocrine protein 7B2 (7B2; gene SCG5)” in human pancreatic islets. (ramzy2020revisitingproinsulinprocessing pages 9-13)

Multiple sources further confirm that 7B2 is a neuroendocrine secretory-pathway protein that functions as a chaperone and endogenous inhibitor for prohormone convertase PC2 (PCSK2), and is widely discussed under the SCG5/7B2 synonymy in endocrine and neuroendocrine contexts. (kikuchi2025expressiondiversityin pages 24-25)

Key concepts and current understanding (definitions, molecular function, and mechanism)

2.1. What kind of protein is SCG5/7B2?

SCG5/7B2 is a neuroendocrine secreted chaperone protein, enriched in neuroendocrine tissues including pituitary, brain, pancreas, and adrenal, and concentrated in regulated secretory granules from which it can be released upon stimulation. (chaplot2020secretedchaperonesin pages 10-11)

It is also described as a sulfated protein synthesized as a precursor and proteolytically processed by a ubiquitous furin-like convertase (i.e., in the secretory pathway). (kikuchi2025expressiondiversityin pages 24-25)

2.2. Primary molecular function: chaperone/cofactor for PC2 (PCSK2) and regulator of its activity

The central, best-established function of SCG5/7B2 is to support the maturation and activity regulation of prohormone convertase 2 (PC2; PCSK2). Specifically, 7B2 binds PC2/proPC2 and is required for enzymatic activation of proPC2; it transiently interacts with proPC2 in the secretory pathway and binds specifically to PC2. (kikuchi2025expressiondiversityin pages 24-25, kikuchi2025expressiondiversityin pages 22-24)

In addition to supporting PC2 maturation/activation, 7B2 can act as an inhibitor of PC2 via its C-terminal peptide: the C-terminal peptide of 7B2 can potently inhibit PC2 in vitro, and mechanistic work indicates this suppression involves PC2/proPC2 regions (including interactions with the pro-domain). (kikuchi2025expressiondiversityin pages 24-25, kikuchi2025expressiondiversityin pages 22-24)

2.3. Processing/cleavage products of 7B2 (SCG5)

A key concept in 7B2 biology is regulated proteolytic processing. Full-length 7B2 (~27 kDa) is cleaved by the Golgi-resident convertase furin to yield a ~21 kDa product; both forms contain a central intrinsically disordered region (IDR). (chaplot2020secretedchaperonesin pages 10-11)

This processing helps separate functional regions, consistent with the notion that 7B2 contains distinct segments responsible for chaperone-like activity vs. inhibitory activity (e.g., C-terminal peptide inhibitory effects on PC2). (chaplot2020secretedchaperonesin pages 10-11, kikuchi2025expressiondiversityin pages 24-25)

2.4. Chaperone-like activity beyond PC2 (extracellular proteostasis concept)

Beyond being a PC2 cofactor, 7B2 is increasingly discussed as a secreted chaperone that may participate in extracellular proteostasis. A review focused on secreted chaperones in neurodegeneration describes 7B2 as one of a small set of neuronal proteins packaged with neuropeptides and released during synaptic activity, with potential client binding influenced by its intrinsically disordered region and oligomerization behavior. (chaplot2020secretedchaperonesin pages 10-11)

Human-islet-focused work further notes prior reports that 7B2 suppresses aggregation/cytotoxicity for amyloidogenic peptides (β-amyloid, synuclein, and islet amyloid polypeptide/IAPP) in culture, supporting a broader chaperone-like role not strictly limited to PC2 maturation. (ramzy2020revisitingproinsulinprocessing pages 13-17)

Subcellular localization and where SCG5 acts

3.1. Secretory pathway and regulated secretory granules

SCG5/7B2 is concentrated in regulated secretory granules and can be released upon stimulation, consistent with its role in endocrine/neuroendocrine peptide processing and regulated secretion. (chaplot2020secretedchaperonesin pages 10-11)

It also participates in secretory-pathway processing: furin cleavage is described as Golgi-resident, placing key maturation events in the Golgi/trans-Golgi network before granule residence and regulated release. (chaplot2020secretedchaperonesin pages 10-11)

3.2. Cell-type localization in human pancreatic islets (α-cells vs β-cells)

In human islets, 7B2 immunoreactivity is detectable in both α- and β-cells, but the intensity is lower in β-cells (contrasting with mice where α and β immunoreactivity is reported to be similar). (ramzy2020revisitingproinsulinprocessing pages 9-13, ramzy2020revisitingproinsulinprocessing pages 13-17)

These conclusions are supported by immunofluorescence images and quantification (alpha-cell to beta-cell intensity ratio for 7B2 in human vs mouse) from the same study’s figures. (ramzy2020revisitingproinsulinprocessing media 8799e6ec, ramzy2020revisitingproinsulinprocessing media defcd976, ramzy2020revisitingproinsulinprocessing media 5e5b3225, ramzy2020revisitingproinsulinprocessing media 324925e1, ramzy2020revisitingproinsulinprocessing media ff79e625)

3.3. Relationship to PC2 localization

PC2 protein and PCSK2 mRNA localize primarily to human α-cells, and PC2 immunoreactivity is not detected (or nearly undetectable) in human β-cells in the referenced human pancreas analyses. (ramzy2020revisitingproinsulinprocessing pages 9-13)

Consistent with this, functional pulse–chase experiments show that PC2 inhibition nearly blocks glucagon production, but does not significantly impair proinsulin processing in human islets, reinforcing that the major physiological PC2-dependent processing step in human islets is proglucagon→glucagon in α-cells rather than β-cell proinsulin maturation. (ramzy2020revisitingproinsulinprocessing pages 9-13)

Pathways and biological processes

4.1. Prohormone/neuropeptide processing pathway via PC2 (PCSK2)

PC2 (PCSK2) is one of the prohormone convertases involved in processing neuropeptide and hormone precursors; SCG5/7B2 is required for PC2 activation and modulates PC2 activity via its C-terminal inhibitory peptide. Thus, SCG5 is positioned as a key regulator of neuroendocrine prohormone processing capacity through the PC2 arm of the proprotein convertase network. (kikuchi2025expressiondiversityin pages 24-25, kikuchi2025expressiondiversityin pages 22-24)

4.2. ACTH/POMC axis implications (primarily supported by genetic models)

Work summarized in a histochemistry-focused paper cites genetic evidence from PC2 and 7B2 null mice analyzing POMC-derived peptide biosynthesis, and notes that 7B2 deficiency can lead to excessive ACTH secretion and lethal phenotypes that can be rescued by adrenalectomy, highlighting a critical in vivo role for 7B2-regulated peptide hormone systems. (kikuchi2025expressiondiversityin pages 25-26, kikuchi2025expressiondiversityin pages 26-26)

Although these are mouse model findings, they help define the conserved physiological systems most sensitive to 7B2/SCG5 loss (POMC/ACTH processing and secretion). (kikuchi2025expressiondiversityin pages 25-26)

Recent developments (prioritizing 2023–2024)

5.1. 2023: Astrocyte secretome and Alzheimer’s-relevant extracellular context

A 2023 astrocyte secretome proteomics study (bioRxiv preprint; posted 2023-01-18; https://doi.org/10.1101/2023.01.18.523916) reports that secretogranin 5 (SCG5; termed SECG5/SCG5 in the text) is among proteins discussed with reported chaperone activity and notes that an Aβ-chaperone function has been reported for SECG5. The authors report decreased secretion of SCG5 in astrocytes exposed to Aβ oligomer-containing medium, and place SCG5 among proteins that have been observed as altered in Alzheimer’s disease cerebrospinal fluid (CSF) in prior proteomic studies. (matafora2023proteomicsofthe pages 6-8)

The same study states that SCG5 has been repeatedly identified in AD vs control CSF studies (noted as present in 4 of 10 studies reviewed in their analysis) and discusses chromogranins/secretogranins as proposed AD biomarkers with decreased CSF levels. (matafora2023proteomicsofthe pages 8-10)

Interpretation: this line of evidence does not redefine SCG5’s canonical intracellular role (PC2 chaperone/inhibitor), but it reinforces the “secreted chaperone/extracellular proteostasis” framing, and motivates interest in SCG5 as a CNS biofluid biomarker candidate in neurodegeneration research. (matafora2023proteomicsofthe pages 6-8, matafora2023proteomicsofthe pages 8-10)

5.2. 2024: Human CF-related diabetes (CFRD) spatial transcriptomics

A 2024 Scientific Reports study (published Oct 2024; https://doi.org/10.1038/s41598-024-76722-1) analyzing human pancreas using spatial transcriptomics reports SCG5 downregulation in both α- and β-cells in cystic fibrosis-related diabetes (CFRD) relative to controls. The authors explicitly connect SCG5/7B2 to its known PC2 chaperone role and hypothesize that reduced SCG5 could impair proglucagon→glucagon processing and processing of islet amyloid polypeptide, thereby contributing to islet dysfunction. (gharib2024cysticfibrosisrelateddiabetes pages 8-9)

Interpretation: this represents a recent application of high-dimensional tissue profiling to place SCG5 within cell-type-specific islet transcriptional programs in a real-world disease context, although quantitative fold-changes and statistical values for SCG5 are referenced as being in supplemental tables rather than shown in the excerpt. (gharib2024cysticfibrosisrelateddiabetes pages 8-9)

Current applications and real-world implementations

6.1. Biomarker research (CSF / secretome / neurodegeneration)

SCG5/7B2 is actively considered in biomarker discovery pipelines in neurodegeneration contexts due to its detectability in CSF and recurring identification in AD vs control CSF proteomics literature, as summarized in the 2023 astrocyte secretome study. (matafora2023proteomicsofthe pages 8-10)

A practical “implementation” angle is that SCG5 can be quantified by mass spectrometry in secretome/CSF proteomics workflows, and that cell-type secretion studies (e.g., astrocytes under Aβ stress) can be used to interpret potential tissue sources of biofluid markers. (matafora2023proteomicsofthe pages 6-8)

6.2. Endocrine/islet pathophysiology interpretation (human pancreas)

In endocrine biology and diabetes research, SCG5 is a tool for understanding PC2-dependent hormone processing. Human pancreas work indicates a strong α-cell localization of the PC2 pathway and confirms that PC2 inhibition affects glucagon production but not proinsulin processing in healthy human islets; these results motivate a human-specific revision of traditional rodent-based assumptions about insulin processing pathways. (ramzy2020revisitingproinsulinprocessing pages 9-13)

The 2024 CFRD spatial transcriptomics study further embeds SCG5 into disease-associated islet transcriptional dysregulation, offering a mechanistic hypothesis (impaired prohormone processing) that can be tested in future functional studies. (gharib2024cysticfibrosisrelateddiabetes pages 8-9)

Expert synthesis and analysis (authoritative interpretation)

7.1. Canonical functional “core”

Across endocrine and neurobiology literature, the most defensible core annotation for SCG5/7B2 is:

• A regulated secretory pathway protein (granule-enriched) that is processed by furin in the Golgi, and that chaperones proPC2/PCSK2 to enable its maturation/activation while also providing an inhibitory C-terminal peptide that can suppress PC2 activity. (chaplot2020secretedchaperonesin pages 10-11, kikuchi2025expressiondiversityin pages 24-25, kikuchi2025expressiondiversityin pages 22-24)

This “dual-function” model (facilitating PC2 maturation while enabling inhibition through its C-terminal peptide) is important for functional annotation because it explains why SCG5 is not simply an on/off switch but a regulator of convertase timing and activity in the secretory pathway. (kikuchi2025expressiondiversityin pages 24-25)

7.2. Human-specific context matters

Human islet biology differs from mouse: in humans, PC2 appears largely α-cell-restricted and β-cells can process proinsulin without PC2-dependent steps; 7B2 is present in β-cells but at lower immunoreactivity than α-cells. This suggests SCG5 in human β-cells may be serving functions beyond PC2 maturation (e.g., broader chaperone roles), or that PC2 expression is post-transcriptionally limited in β-cells. (ramzy2020revisitingproinsulinprocessing pages 9-13, ramzy2020revisitingproinsulinprocessing pages 13-17)

Relevant quantitative/statistical data points (as available in retrieved sources)

• CSF concentration: A review reports CSF levels of 7B2 of approximately 3 ng/mL (0.14 nM) and that levels decline with age. (chaplot2020secretedchaperonesin pages 10-11)

• Human islet processing dependence: In human islets, PC2 inhibition produces near total blockade of glucagon production but does not significantly change proinsulin processing in pulse–chase experiments. (ramzy2020revisitingproinsulinprocessing pages 9-13)

• Enzymology context: PC2 is noted to be ~80–100× more catalytically active than PC1/3 (as cited in the human islet study), which is relevant when interpreting why small amounts of PC2 could have outsized processing effects in cell types where it is present. (ramzy2020revisitingproinsulinprocessing pages 9-13)

• 2023 proteomics summary statistic: The 2023 astrocyte secretome study reports 45 proteins with altered secretion in response to Aβ oligomer-containing medium (23 up; 22 down), within which SCG5 is discussed in relation to chaperone activity and biomarker context, though the excerpt does not provide SCG5-specific fold-change statistics. (matafora2023proteomicsofthe pages 8-10)

Limitations of the current evidence base (important for functional annotation)

• Some of the mechanistic endocrine phenotypes summarized (e.g., lethality/ACTH axis changes) rely heavily on mouse genetic models and may not map one-to-one to human physiology, though the underlying PC2/7B2 interaction is considered conserved. (kikuchi2025expressiondiversityin pages 25-26, kikuchi2025expressiondiversityin pages 26-26)

• Recent 2023–2024 “omics” studies that mention SCG5 (astrocyte secretome; CFRD spatial transcriptomics) often emphasize global patterns; SCG5-specific quantitative performance (effect sizes, diagnostic AUCs, etc.) is not present in the excerpts retrieved here and may reside in supplementary tables or follow-up peer-reviewed articles. (gharib2024cysticfibrosisrelateddiabetes pages 8-9, matafora2023proteomicsofthe pages 8-10)

Key references (publication date + URL)

• Ramzy A, Asadi A, Kieffer TJ. “Revisiting Proinsulin Processing: Evidence That Human β-Cells Process Proinsulin With Prohormone Convertase (PC) 1/3 but Not PC2.” Diabetes. Published Apr 2020. https://doi.org/10.2337/db19-0276 (ramzy2020revisitingproinsulinprocessing pages 9-13)

• Chaplot K, Jarvela TS, Lindberg I. “Secreted Chaperones in Neurodegeneration.” Frontiers in Aging Neuroscience. Published Aug 2020. https://doi.org/10.3389/fnagi.2020.00268 (chaplot2020secretedchaperonesin pages 10-11)

• Matafora V et al. “Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric Aβ.” bioRxiv preprint. Posted Jan 2023. https://doi.org/10.1101/2023.01.18.523916 (matafora2023proteomicsofthe pages 6-8)

• Gharib SA et al. “Cystic fibrosis-related diabetes is associated with reduced islet protein expression of GLP-1 receptor and perturbation of cell-specific transcriptional programs.” Scientific Reports. Published Oct 2024. https://doi.org/10.1038/s41598-024-76722-1 (gharib2024cysticfibrosisrelateddiabetes pages 8-9)

Evidence-supported visual references

• Immunostaining panels and quantification for PC2 and 7B2/SCG5 in human vs mouse islets (from Ramzy et al. 2020 figures and supplemental figure crops). (ramzy2020revisitingproinsulinprocessing media 8799e6ec, ramzy2020revisitingproinsulinprocessing media defcd976, ramzy2020revisitingproinsulinprocessing media 5e5b3225, ramzy2020revisitingproinsulinprocessing media 324925e1, ramzy2020revisitingproinsulinprocessing media ff79e625)

References

(ramzy2020revisitingproinsulinprocessing pages 9-13): Adam Ramzy, Ali Asadi, and Timothy J. Kieffer. Revisiting proinsulin processing: evidence that human β-cells process proinsulin with prohormone convertase (pc) 1/3 but not pc2. Diabetes, 69:1451-1462, Apr 2020. URL: https://doi.org/10.2337/db19-0276, doi:10.2337/db19-0276. This article has 69 citations and is from a highest quality peer-reviewed journal.
(kikuchi2025expressiondiversityin pages 24-25): Shota Kikuchi, Seiji Torii, Masahiro Hosaka, Tadashi Yasui, and Hiroshi Gomi. Expression diversity in endocrine cells and between species revealed by novel synthetic peptide antibodies recognizing the neuroendocrine protein 7b2. Journal of Histochemistry & Cytochemistry, 73(7–8):289-314, Aug 2025. URL: https://doi.org/10.1369/00221554251365996, doi:10.1369/00221554251365996. This article has 0 citations and is from a peer-reviewed journal.
(chaplot2020secretedchaperonesin pages 10-11): Kriti Chaplot, Timothy S. Jarvela, and Iris Lindberg. Secreted chaperones in neurodegeneration. Frontiers in Aging Neuroscience, Aug 2020. URL: https://doi.org/10.3389/fnagi.2020.00268, doi:10.3389/fnagi.2020.00268. This article has 64 citations and is from a peer-reviewed journal.
(kikuchi2025expressiondiversityin pages 22-24): Shota Kikuchi, Seiji Torii, Masahiro Hosaka, Tadashi Yasui, and Hiroshi Gomi. Expression diversity in endocrine cells and between species revealed by novel synthetic peptide antibodies recognizing the neuroendocrine protein 7b2. Journal of Histochemistry & Cytochemistry, 73(7–8):289-314, Aug 2025. URL: https://doi.org/10.1369/00221554251365996, doi:10.1369/00221554251365996. This article has 0 citations and is from a peer-reviewed journal.
(ramzy2020revisitingproinsulinprocessing pages 13-17): Adam Ramzy, Ali Asadi, and Timothy J. Kieffer. Revisiting proinsulin processing: evidence that human β-cells process proinsulin with prohormone convertase (pc) 1/3 but not pc2. Diabetes, 69:1451-1462, Apr 2020. URL: https://doi.org/10.2337/db19-0276, doi:10.2337/db19-0276. This article has 69 citations and is from a highest quality peer-reviewed journal.
(ramzy2020revisitingproinsulinprocessing media 8799e6ec): Adam Ramzy, Ali Asadi, and Timothy J. Kieffer. Revisiting proinsulin processing: evidence that human β-cells process proinsulin with prohormone convertase (pc) 1/3 but not pc2. Diabetes, 69:1451-1462, Apr 2020. URL: https://doi.org/10.2337/db19-0276, doi:10.2337/db19-0276. This article has 69 citations and is from a highest quality peer-reviewed journal.
(ramzy2020revisitingproinsulinprocessing media defcd976): Adam Ramzy, Ali Asadi, and Timothy J. Kieffer. Revisiting proinsulin processing: evidence that human β-cells process proinsulin with prohormone convertase (pc) 1/3 but not pc2. Diabetes, 69:1451-1462, Apr 2020. URL: https://doi.org/10.2337/db19-0276, doi:10.2337/db19-0276. This article has 69 citations and is from a highest quality peer-reviewed journal.
(ramzy2020revisitingproinsulinprocessing media 5e5b3225): Adam Ramzy, Ali Asadi, and Timothy J. Kieffer. Revisiting proinsulin processing: evidence that human β-cells process proinsulin with prohormone convertase (pc) 1/3 but not pc2. Diabetes, 69:1451-1462, Apr 2020. URL: https://doi.org/10.2337/db19-0276, doi:10.2337/db19-0276. This article has 69 citations and is from a highest quality peer-reviewed journal.
(ramzy2020revisitingproinsulinprocessing media 324925e1): Adam Ramzy, Ali Asadi, and Timothy J. Kieffer. Revisiting proinsulin processing: evidence that human β-cells process proinsulin with prohormone convertase (pc) 1/3 but not pc2. Diabetes, 69:1451-1462, Apr 2020. URL: https://doi.org/10.2337/db19-0276, doi:10.2337/db19-0276. This article has 69 citations and is from a highest quality peer-reviewed journal.
(ramzy2020revisitingproinsulinprocessing media ff79e625): Adam Ramzy, Ali Asadi, and Timothy J. Kieffer. Revisiting proinsulin processing: evidence that human β-cells process proinsulin with prohormone convertase (pc) 1/3 but not pc2. Diabetes, 69:1451-1462, Apr 2020. URL: https://doi.org/10.2337/db19-0276, doi:10.2337/db19-0276. This article has 69 citations and is from a highest quality peer-reviewed journal.
(kikuchi2025expressiondiversityin pages 25-26): Shota Kikuchi, Seiji Torii, Masahiro Hosaka, Tadashi Yasui, and Hiroshi Gomi. Expression diversity in endocrine cells and between species revealed by novel synthetic peptide antibodies recognizing the neuroendocrine protein 7b2. Journal of Histochemistry & Cytochemistry, 73(7–8):289-314, Aug 2025. URL: https://doi.org/10.1369/00221554251365996, doi:10.1369/00221554251365996. This article has 0 citations and is from a peer-reviewed journal.
(kikuchi2025expressiondiversityin pages 26-26): Shota Kikuchi, Seiji Torii, Masahiro Hosaka, Tadashi Yasui, and Hiroshi Gomi. Expression diversity in endocrine cells and between species revealed by novel synthetic peptide antibodies recognizing the neuroendocrine protein 7b2. Journal of Histochemistry & Cytochemistry, 73(7–8):289-314, Aug 2025. URL: https://doi.org/10.1369/00221554251365996, doi:10.1369/00221554251365996. This article has 0 citations and is from a peer-reviewed journal.
(matafora2023proteomicsofthe pages 6-8): Vittoria Matafora, Alena Gorb, Wendy Noble, Angela Bachi, Beatriz Gomez Perez-Nievas, and Maria Jimenez-Sanchez. Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric aß. bioRxiv, Jan 2023. URL: https://doi.org/10.1101/2023.01.18.523916, doi:10.1101/2023.01.18.523916. This article has 1 citations.
(matafora2023proteomicsofthe pages 8-10): Vittoria Matafora, Alena Gorb, Wendy Noble, Angela Bachi, Beatriz Gomez Perez-Nievas, and Maria Jimenez-Sanchez. Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric aß. bioRxiv, Jan 2023. URL: https://doi.org/10.1101/2023.01.18.523916, doi:10.1101/2023.01.18.523916. This article has 1 citations.
(gharib2024cysticfibrosisrelateddiabetes pages 8-9): Sina A. Gharib, Rachna Vemireddy, Joseph J. Castillo, Brendy S. Fountaine, Theo K. Bammler, James W. MacDonald, Rebecca L. Hull-Meichle, and Sakeneh Zraika. Cystic fibrosis-related diabetes is associated with reduced islet protein expression of glp-1 receptor and perturbation of cell-specific transcriptional programs. Scientific Reports, Oct 2024. URL: https://doi.org/10.1038/s41598-024-76722-1, doi:10.1038/s41598-024-76722-1. This article has 8 citations and is from a peer-reviewed journal.

Citations

ramzy2020revisitingproinsulinprocessing pages 9-13
kikuchi2025expressiondiversityin pages 24-25
chaplot2020secretedchaperonesin pages 10-11
ramzy2020revisitingproinsulinprocessing pages 13-17
kikuchi2025expressiondiversityin pages 25-26
matafora2023proteomicsofthe pages 6-8
matafora2023proteomicsofthe pages 8-10
gharib2024cysticfibrosisrelateddiabetes pages 8-9
kikuchi2025expressiondiversityin pages 22-24
kikuchi2025expressiondiversityin pages 26-26
https://doi.org/10.1101/2023.01.18.523916
https://doi.org/10.1038/s41598-024-76722-1
https://doi.org/10.2337/db19-0276
https://doi.org/10.3389/fnagi.2020.00268
https://doi.org/10.2337/db19-0276,
https://doi.org/10.1369/00221554251365996,
https://doi.org/10.3389/fnagi.2020.00268,
https://doi.org/10.1101/2023.01.18.523916,
https://doi.org/10.1038/s41598-024-76722-1,

📄 View Raw YAML

id: P05408
gene_symbol: SCG5
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: SCG5 (also known as neuroendocrine protein 7B2 or secretogranin V) encodes
  a highly conserved secretory protein selectively expressed in neuroendocrine cells.
  It functions as a specific molecular chaperone for proprotein convertase 2 (PCSK2/PC2),
  binding to inactive proPC2 in the endoplasmic reticulum and facilitating its transport
  through the secretory pathway to compartments where PC2 is proteolytically matured
  and activated. Critically, 7B2 is not involved in PC2 folding; rather, it acts after
  PC2 has folded, serving as a transport facilitator and preventing premature activation.
  The C-terminal peptide of 7B2 also functions as an inhibitor of PC2 enzymatic activity
  in vitro. Full-length 7B2 (~27 kDa) is cleaved by the Golgi-resident convertase furin
  to yield a ~21 kDa product; both forms contain a central intrinsically disordered
  region (IDR) that influences client binding and oligomerization behavior
  (DOI:10.3389/fnagi.2020.00268). Beyond PC2 regulation, 7B2 acts as a broader secreted
  chaperone that suppresses aggregation and cytotoxicity of amyloidogenic peptides
  including beta-amyloid, alpha-synuclein, and islet amyloid polypeptide (IAPP)
  (DOI:10.2337/db19-0276, DOI:10.3389/fnagi.2020.00268). In human pancreatic islets,
  PC2 localizes primarily to alpha-cells, and 7B2 immunoreactivity is lower in beta-cells
  than alpha-cells, contrasting with mouse islets where both cell types show similar
  expression. Functional pulse-chase experiments demonstrate that PC2 inhibition nearly
  blocks glucagon production but does not significantly impair proinsulin processing in
  human islets, indicating the major physiological PC2/7B2-dependent processing step in
  human islets is proglucagon-to-glucagon in alpha-cells rather than beta-cell proinsulin
  maturation (DOI:10.2337/db19-0276). CSF levels of 7B2 are approximately 3 ng/mL
  (0.14 nM) and decline with age, and SCG5 has been recurrently identified in Alzheimer's
  disease vs. control CSF proteomics studies (DOI:10.3389/fnagi.2020.00268). Spatial
  transcriptomics of human pancreas in cystic fibrosis-related diabetes (CFRD) reveals
  SCG5 downregulation in both alpha- and beta-cells, suggesting impaired prohormone
  processing as a contributor to islet dysfunction in CFRD
  (DOI:10.1038/s41598-024-76722-1).
alternative_products:
- name: '1'
  id: P05408-1
- name: '2'
  id: P05408-2
  sequence_note: VSP_011754
existing_annotations:
- term:
    id: GO:0030234
    label: enzyme regulator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9348280
      supporting_text: 7B2 acts as a helper protein involved in proPC2 transport and
        is required in the proPC2 activation process
    - reference_id: PMID:11439082
      supporting_text: Its C-terminal peptide can inhibit PC2 in vitro and may
        contribute to keep the enzyme transiently inactive in vivo
- term:
    id: GO:0046883
    label: regulation of hormone secretion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:11439082
      supporting_text: 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
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:11439082
      supporting_text: 7B2 is an acidic protein residing in the secretory granules
        of neuroendocrine cells
- term:
    id: GO:0007218
    label: neuropeptide signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:11439082
      supporting_text: In neuroendocrine cells, 7B2 functions as a specific
        chaperone for the proprotein convertase (PC) 2
- term:
    id: GO:0030141
    label: secretory granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    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.
    action: ACCEPT
    reason: Localization of SCG5/7B2 to secretory granules is well established and
      is consistent with its known biology as a neuroendocrine secretory pathway
      protein.
    supported_by:
    - reference_id: PMID:3134253
      supporting_text: This protein of unknown function, which is sorted to secretory
        granules, appears to be present selectively in neurons and endocrine cells
    - reference_id: PMID:11439082
      supporting_text: 7B2 is an acidic protein residing in the secretory granules
        of neuroendocrine cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0004857
    label: enzyme inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0004867
      label: serine-type endopeptidase inhibitor activity
    supported_by:
    - reference_id: PMID:9348280
      supporting_text: The identity of this activity as PC2 was demonstrated by its
        complete inhibition by the 7B2 CT peptide
    - reference_id: PMID:11439082
      supporting_text: Its C-terminal peptide can inhibit PC2 in vitro and may
        contribute to keep the enzyme transiently inactive in vivo
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: REMOVE
    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.
    supported_by:
    - reference_id: PMID:11439082
      supporting_text: 7B2 is an acidic protein residing in the secretory granules
        of neuroendocrine cells
    - reference_id: PMID:7913882
      supporting_text: 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
- term:
    id: GO:0006886
    label: intracellular protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9348280
      supporting_text: Under experimental conditions that prevent propeptide
        cleavage, 7B2 expression increased proPC2 transport to the Golgi
    - reference_id: PMID:9348280
      supporting_text: we propose that 7B2 stabilizes a transport-competent
        conformation of proPC2. This stabilization results in an increase in
        transport to the Golgi
- term:
    id: GO:0016486
    label: peptide hormone processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:9348280
      supporting_text: 7B2 is required for the productive cleavage of the
        propeptide, i.e., for the generation of active mature PC2
    - reference_id: PMID:11439082
      supporting_text: 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
- term:
    id: GO:0046883
    label: regulation of hormone secretion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Duplicate of the IBA annotation to GO:0046883. The IEA transfer is
      consistent with the IBA annotation. This is a secondary downstream role.
    supported_by:
    - reference_id: PMID:11439082
      supporting_text: 7B2-null mutants die early in life from Cushing's disease
        due to corticotropin ('ACTH') hypersecretion by the neurointermediate lobe
- term:
    id: GO:0004857
    label: enzyme inhibitor activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0004867
      label: serine-type endopeptidase inhibitor activity
    supported_by:
    - reference_id: PMID:9348280
      supporting_text: The identity of this activity as PC2 was demonstrated by its
        complete inhibition by the 7B2 CT peptide
    - reference_id: PMID:11439082
      supporting_text: Its C-terminal peptide can inhibit PC2 in vitro and may
        contribute to keep the enzyme transiently inactive in vivo
- term:
    id: GO:0006886
    label: intracellular protein transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9348280
      supporting_text: Under experimental conditions that prevent propeptide
        cleavage, 7B2 expression increased proPC2 transport to the Golgi
- term:
    id: GO:0016486
    label: peptide hormone processing
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Same rationale as the IEA annotation. Indirect contribution to peptide
      hormone processing through enabling PC2 activation.
    supported_by:
    - reference_id: PMID:9348280
      supporting_text: 7B2 is required for the productive cleavage of the
        propeptide, i.e., for the generation of active mature PC2
- term:
    id: GO:0030141
    label: secretory granule
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:3134253
      supporting_text: This protein of unknown function, which is sorted to
        secretory granules, appears to be present selectively in neurons and
        endocrine cells
    - reference_id: PMID:11439082
      supporting_text: 7B2 is an acidic protein residing in the secretory granules
        of neuroendocrine cells
- term:
    id: GO:0046883
    label: regulation of hormone secretion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:11439082
      supporting_text: 7B2-null mutants die early in life from Cushing's disease
        due to corticotropin ('ACTH') hypersecretion by the neurointermediate lobe
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:7913882
  review:
    summary: GO:0051082 is being obsoleted (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.
    action: MODIFY
    reason: The annotation to GO:0051082 (unfolded protein binding) is incorrect for
      SCG5/7B2. The term is being obsoleted (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_replacement_terms:
    - id: GO:0140318
      label: protein transporter activity
    additional_reference_ids:
    - PMID:9348280
    - PMID:11439082
    supported_by:
    - reference_id: PMID:7913882
      supporting_text: 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
    - reference_id: PMID:9348280
      supporting_text: 7B2 is not involved in the early steps of proPC2 folding, and
        that proPC2 must fold before binding 7B2
    - reference_id: PMID:9348280
      supporting_text: rather than promoting proPC2 folding, 7B2 acts as a helper
        protein involved in proPC2 transport and is required in the proPC2 activation
        process
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7913882
  review:
    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).
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:7913882
      supporting_text: recombinant 7B2 specifically associates with prohormone
        convertase PC2
    - reference_id: PMID:7913882
      supporting_text: the precursor form of 7B2 interacts with the proform of PC2
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: TAS
  original_reference_id: PMID:3134253
  review:
    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.
    action: REMOVE
    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.
    supported_by:
    - reference_id: PMID:3134253
      supporting_text: the presence of three regions homologous to GTP-binding
        domains giving 7B2 structural characteristics of a GTP-binding protein
- term:
    id: GO:0008047
    label: enzyme activator activity
  evidence_type: ISS
  original_reference_id: PMID:9348280
  review:
    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.
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:9348280
      supporting_text: In vitro, 7B2 was required for proPC2 activation at an
        acidic pH
    - reference_id: PMID:9348280
      supporting_text: 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
    - reference_id: PMID:11439082
      supporting_text: 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
core_functions:
- description: >-
    SCG5/7B2 functions as a specific molecular chaperone/transporter for proprotein
    convertase 2 (PCSK2/PC2). The N-terminal domain binds folded proPC2 in the ER
    and facilitates its transport through the secretory pathway to compartments where
    PC2 is proteolytically matured and activated. Without 7B2, proPC2 propeptide
    cleavage produces inactive enzyme. 7B2 is required for productive PC2 activation.
    Full-length 7B2 (~27 kDa) is cleaved by Golgi-resident furin to yield a ~21 kDa
    product, and both forms contain a central intrinsically disordered region (IDR)
    that influences client binding and oligomerization (DOI:10.3389/fnagi.2020.00268).
    In human islets, the major physiological PC2/7B2-dependent processing step is
    proglucagon-to-glucagon in alpha-cells rather than beta-cell proinsulin maturation
    (DOI:10.2337/db19-0276). Beyond PC2, 7B2 also suppresses aggregation of amyloidogenic
    peptides including beta-amyloid, alpha-synuclein, and IAPP, consistent with a
    broader secreted chaperone role in extracellular proteostasis
    (DOI:10.3389/fnagi.2020.00268, DOI:10.2337/db19-0276).
  molecular_function:
    id: GO:0140318
    label: protein transporter activity
  directly_involved_in:
    - id: GO:0006886
      label: intracellular protein transport
  locations:
    - id: GO:0005788
      label: endoplasmic reticulum lumen
    - id: GO:0030141
      label: secretory granule
  supported_by:
    - reference_id: PMID:9348280
      supporting_text: >-
        rather than promoting proPC2 folding, 7B2 acts as a helper
        protein involved in proPC2 transport and is required in the proPC2 activation
        process
    - reference_id: PMID:9348280
      supporting_text: >-
        Under experimental conditions that prevent propeptide
        cleavage, 7B2 expression increased proPC2 transport to the Golgi
- description: >-
    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.
  molecular_function:
    id: GO:0008047
    label: enzyme activator activity
  directly_involved_in:
    - id: GO:0006886
      label: intracellular protein transport
  locations:
    - id: GO:0030141
      label: secretory granule
  supported_by:
    - reference_id: PMID:9348280
      supporting_text: >-
        In vitro, 7B2 was required for proPC2 activation at an
        acidic pH
    - reference_id: PMID:9348280
      supporting_text: >-
        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
- description: >-
    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.
  molecular_function:
    id: GO:0004867
    label: serine-type endopeptidase inhibitor activity
  locations:
    - id: GO:0030141
      label: secretory granule
  supported_by:
    - reference_id: PMID:9348280
      supporting_text: >-
        The identity of this activity as PC2 was demonstrated by its
        complete inhibition by the 7B2 CT peptide
    - reference_id: PMID:11439082
      supporting_text: >-
        Its C-terminal peptide can inhibit PC2 in vitro and may
        contribute to keep the enzyme transiently inactive in vivo
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:3134253
  title: Cloning and sequence analysis of human pituitary cDNA encoding the novel
    polypeptide 7B2.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:7913882
  title: 7B2 is a neuroendocrine chaperone that transiently interacts with prohormone
    convertase PC2 in the secretory pathway.
  findings: []
- id: PMID:9348280
  title: Mechanism of the facilitation of PC2 maturation by 7B2 involvement in ProPC2
    transport and activation but not folding.
  findings: []
- id: PMID:11439082
  title: Neuroendocrine secretory protein 7B2 structure, expression and functions.
  findings: []
- id: DOI:10.3389/fnagi.2020.00268
  title: Secreted Chaperones in Neurodegeneration
  findings:
  - statement: 7B2 is a neuroendocrine secreted chaperone protein packaged with neuropeptides
      and released during synaptic activity, with client binding influenced by its
      intrinsically disordered region and oligomerization behavior.
  - statement: Full-length 7B2 (~27 kDa) is cleaved by the Golgi-resident convertase
      furin to yield a ~21 kDa product; both forms contain a central intrinsically
      disordered region (IDR).
  - statement: CSF levels of 7B2 are approximately 3 ng/mL (0.14 nM) and decline
      with age, and SCG5 has been recurrently identified in AD vs control CSF proteomics
      studies.
- id: DOI:10.2337/db19-0276
  title: Revisiting Proinsulin Processing -- Evidence That Human Beta-Cells Process
    Proinsulin With Prohormone Convertase (PC) 1/3 but Not PC2
  findings:
  - statement: In human islets, PC2 immunoreactivity is primarily in alpha-cells and
      nearly undetectable in beta-cells, contrasting with mouse islets where both cell
      types express PC2.
  - statement: PC2 inhibition nearly blocks glucagon production but does not significantly
      change proinsulin processing in pulse-chase experiments on human islets.
  - statement: 7B2 immunoreactivity is detectable in both alpha- and beta-cells in
      human islets, but the intensity is lower in beta-cells than alpha-cells.
  - statement: Prior reports indicate that 7B2 suppresses aggregation and cytotoxicity
      for amyloidogenic peptides including beta-amyloid, synuclein, and IAPP.
- id: DOI:10.1101/2023.01.18.523916
  title: Proteomics of the astrocyte secretome reveals changes in their response to
    soluble oligomeric Abeta
  findings:
  - statement: SCG5 is among proteins with reported chaperone activity whose secretion
      is altered in astrocytes exposed to Abeta oligomer-containing medium.
  - statement: SCG5 has been identified in 4 of 10 AD vs control CSF proteomics studies
      reviewed, and chromogranins/secretogranins are proposed AD biomarkers with decreased
      CSF levels.
- id: DOI:10.1038/s41598-024-76722-1
  title: Cystic fibrosis-related diabetes is associated with reduced islet protein
    expression of GLP-1 receptor and perturbation of cell-specific transcriptional
    programs
  findings:
  - statement: Spatial transcriptomics of human pancreas in CFRD reveals SCG5 downregulation
      in both alpha- and beta-cells, with the authors connecting SCG5/7B2 to its known
      PC2 chaperone role and hypothesizing that reduced SCG5 could impair proglucagon-to-glucagon
      processing and IAPP processing.

SCG5

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

📚 Additional Documentation

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Question

Gene Research for Functional Annotation

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Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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