Neuroendocrine secretory protein 7B2: structure, expression and functions

Abstract

7B2 is an acidic protein residing in the secretory granules of neuroendocrine cells. Its sequence has been elucidated in many phyla and species. It shows high similarity among mammals. A Pro-Pro-Asn-Pro-Cys-Pro polyproline motif is its most conserved feature, being carried by both vertebrate and invertebrate sequences. It is biosynthesized as a precursor protein that is cleaved into an N-terminal fragment and a C-terminal peptide. In neuroendocrine cells, 7B2 functions as a specific chaperone for the proprotein convertase (PC) 2. Through the sequence around its Pro-Pro-Asn-Pro-Cys-Pro motif, 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. Its C-terminal peptide can inhibit PC2 in vitro and may contribute to keep the enzyme transiently inactive in vivo. 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. Interestingly, 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. The mechanism of this regulation is yet to be elucidated. 7B2 has been shown to be a good marker of several neuroendocrine cell dysfunctions in humans. The possibility that anomalies in its structure and expression could be aetiological causes of some of these dysfunctions warrants investigation.

Global analysis of neuropeptides in cestodes identifies Attachin, a SIFamide homolog, as a stimulant of parasite motility and attachment

“…Interestingly, we also found evidence of proteolytic processing of HmN_000798200, which is the H. microstoma homolog of 7B2, a protein that functions as a specific chaperone and inhibitor of the proprotein convertase PC2 (Mbikay et al, 2001). Cleavage occurred at mono and dibasic sites in the C‐terminal region, in positions which could correspond to similar processing steps that cleave the inhibiting C‐terminal peptide, and that eliminate its inhibitory activity in other animals (Hoshino & Lindberg, 2012) (Figure S3).…”

Global analysis of neuropeptides in cestodes identifies Attachin, a SIFamide homolog, as a stimulant of parasite motility and attachment

“…Interestingly, we also found evidence of proteolytic processing of HmN_000798200, which is the H. microstoma homolog of 7B2, a protein that functions as a specific chaperone and inhibitor of the proprotein convertase PC2 (Mbikay et al, 2001). Cleavage occurred at mono and dibasic sites in the C‐terminal region, in positions which could correspond to similar processing steps that cleave the inhibiting C‐terminal peptide, and that eliminate its inhibitory activity in other animals (Hoshino & Lindberg, 2012) (Figure S3).…”

A single-cell atlas of the Culex tarsalis midgut during West Nile virus infection

“…However, these neuropeptides/neuropeptide receptors were found to have very low and nonspecific expression in the EE population ( S3A Fig ). The EE population was significantly enriched for canonical neuroendocrine genes ( IA2 , and SCG5 ) [ 33 , 34 ] and Syt1 , and showed low and nonspecific expression of Syt4 , Syt6 , Syx1A and nSyb (genes associated with vesicle docking and secretion) ( Figs 2D and S3A ) [ 14 , 35 ]. Interestingly, the EE population showed strong enrichment for NEUROD6 , an ortholog for neurogenic differentiation factor 4 in Ae.…”

linc-mipep and linc-wrb encode micropeptides that regulate chromatin accessibility in vertebrate-specific neural cells

“…Indeed, we found that some of the differentially regulated genes in single-cell analyses are known to be involved in NMDA receptor and glucocorticoid receptor signaling. For example, fkbp5 , which is associated with glucocorticoid signaling, showed reduced expression in linc-mipep mutant OPCs, and scg5 , which can mediate stress responses ( Cao-Lei et al, 2014 ; Mbikay et al, 2001 ), showed reduced expression broadly ( Figure 4H ; Figure 4—figure supplement 7 ). These genes also showed changed chromatin accessibility in the linc-mipep;linc-wrb double mutant brains ( Figure 4—figure supplement 6D and E).…”

Global analysis of neuropeptides in cestodes identifies Attachin, a SIFamide homolog, as a stimulant of parasite motility and attachment

“…Interestingly, we also found evidence of proteolytic processing of HmN_000798200, which is the H. microstoma homolog of 7B2, a protein that functions as a specific chaperone and inhibitor of the proprotein convertase PC2 (Mbikay et al, 2001). Cleavage occurred at mono and dibasic sites in the C‐terminal region, in positions which could correspond to similar processing steps that cleave the inhibiting C‐terminal peptide, and that eliminate its inhibitory activity in other animals (Hoshino & Lindberg, 2012) (Figure S3).…”

A single-cell atlas of the Culex tarsalis midgut during West Nile virus infection

“…However, these neuropeptides/neuropeptide receptors were found to have very low and nonspecific expression in the EE population ( S3A Fig ). The EE population was significantly enriched for canonical neuroendocrine genes ( IA2 , and SCG5 ) [ 33 , 34 ] and Syt1 , and showed low and nonspecific expression of Syt4 , Syt6 , Syx1A and nSyb (genes associated with vesicle docking and secretion) ( Figs 2D and S3A ) [ 14 , 35 ]. Interestingly, the EE population showed strong enrichment for NEUROD6 , an ortholog for neurogenic differentiation factor 4 in Ae.…”

linc-mipep and linc-wrb encode micropeptides that regulate chromatin accessibility in vertebrate-specific neural cells

“…Indeed, we found that some of the differentially regulated genes in single-cell analyses are known to be involved in NMDA receptor and glucocorticoid receptor signaling. For example, fkbp5 , which is associated with glucocorticoid signaling, showed reduced expression in linc-mipep mutant OPCs, and scg5 , which can mediate stress responses ( Cao-Lei et al, 2014 ; Mbikay et al, 2001 ), showed reduced expression broadly ( Figure 4H ; Figure 4—figure supplement 7 ). These genes also showed changed chromatin accessibility in the linc-mipep;linc-wrb double mutant brains ( Figure 4—figure supplement 6D and E).…”

Global analysis of neuropeptides in cestodes identifies Attachin, a SIFamide homolog, as a stimulant of parasite motility and attachment

“…Interestingly, we also found evidence of proteolytic processing of HmN_000798200, which is the H. microstoma homolog of 7B2, a protein that functions as a specific chaperone and inhibitor of the proprotein convertase PC2 (Mbikay et al, 2001). Cleavage occurred at mono and dibasic sites in the C‐terminal region, in positions which could correspond to similar processing steps that cleave the inhibiting C‐terminal peptide, and that eliminate its inhibitory activity in other animals (Hoshino & Lindberg, 2012) (Figure S3).…”

A single-cell atlas of the Culex tarsalis midgut during West Nile virus infection

“…However, these neuropeptides/neuropeptide receptors were found to have very low and nonspecific expression in the EE population ( S3A Fig ). The EE population was significantly enriched for canonical neuroendocrine genes ( IA2 , and SCG5 ) [ 33 , 34 ] and Syt1 , and showed low and nonspecific expression of Syt4 , Syt6 , Syx1A and nSyb (genes associated with vesicle docking and secretion) ( Figs 2D and S3A ) [ 14 , 35 ]. Interestingly, the EE population showed strong enrichment for NEUROD6 , an ortholog for neurogenic differentiation factor 4 in Ae.…”

linc-mipep and linc-wrb encode micropeptides that regulate chromatin accessibility in vertebrate-specific neural cells

“…Indeed, we found that some of the differentially regulated genes in single-cell analyses are known to be involved in NMDA receptor and glucocorticoid receptor signaling. For example, fkbp5 , which is associated with glucocorticoid signaling, showed reduced expression in linc-mipep mutant OPCs, and scg5 , which can mediate stress responses ( Cao-Lei et al, 2014 ; Mbikay et al, 2001 ), showed reduced expression broadly ( Figure 4H ; Figure 4—figure supplement 7 ). These genes also showed changed chromatin accessibility in the linc-mipep;linc-wrb double mutant brains ( Figure 4—figure supplement 6D and E).…”