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0  structures 88  species 0  interactions 117  sequences 3  architectures

Family: Secretogranin_V (PF05281)

Summary: Neuroendocrine protein 7B2 precursor (Secretogranin V)

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Neuroendocrine protein 7B2 precursor (Secretogranin V) Provide feedback

The neuroendocrine protein 7B2 has a critical role in the proteolytic conversion and activation of proPC2, the enzyme responsible for the proteolytic conversion of many peptide hormone precursors. The 7B2 protein acts as an intracellular binding protein for proPC2, facilitates its maturation, and is required for its enzymatic activity. Processing of many important peptide precursors does not occur in 7B2 nulls. 7B2 null mice exhibit a unique form of Cushing's disease with many atypical symptoms, such as hypoglycemia [1].

Literature references

  1. Sarac MS, Zieske AW, Lindberg I; , Endocrinology 2002;143:2324-2332.: The lethal form of Cushing's in 7B2 null mice is caused by multiple metabolic and hormonal abnormalities. PUBMED:12021197 EPMC:12021197


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR007945

Mature peptide hormones and neuropeptides are typically synthesised from much larger precursors and require several post-translational processing steps--including proteolytic cleavage--for the formation of the bioactive species. The subtilisin-related proteolytic enzymes that accomplish neuroendocrine-specific cleavages are known as prohormone convertases 1 and 2 (PC1 and PC2), which belong to MEROPS peptidase family S8B. The cell biology of these proteases within the regulated secretory pathway of neuroendocrine cells is complex, and they are themselves initially synthesised as inactive precursor molecules. ProPC1 propeptide cleavage occurs rapidly in the endoplasmic reticulum, yet its major site of action on prohormones takes place later in the secretory pathway. PC1 undergoes an interesting carboxyl terminal processing event whose function appears to be to activate the enzyme. ProPC2, on the other hand, exhibits comparatively long initial folding times and exits the endoplasmic reticulum without propeptide cleavage, in association with the neuroendocrine-specific protein 7B2. Once the proPC2/7B2 complex arrives at the trans-Golgi network, 7B2 is internally cleaved into two domains, the 21kDa fragment and a carboxy-terminal 31 residue peptide. PC2 propeptide removal occurs in the maturing secretory granule, most likely through autocatalysis, and 7B2 association does not appear to be directly required for this cleavage event. However, if proPC2 has not encountered 7B2 intracellularly, it cannot generate a catalytically active mature species. The molecular mechanism behind the intriguing intracellular association of 7B2 and proPC2 is still unknown, but may involve conformational rearrangement or stabilisation of a proPC2 conformer mediated by a 36-residue internal segment of 21kDa 7B2.

This family represents, 7B2 (secretogranin V), which is the molecular escort protein for PC2. 7B2 is a bifunctional protein with an N-terminal activation domain and a C-terminal inhibitory domain (MEROPS inhibitor family I21, clan I-) separated by a furin cleavage site [PUBMED:10506829]. Although 7B2 represents a potent inhibitor of PC2, there is an absolute requirement of 7B2 for the activation of PC2, which is synthesised as a zymogen. Both the full length, 27 kDa, and the C-terminal peptide (CT domain) derived from intramolecular cleavage of 7B2 are potent inhibitors of PC2. Studies have shown that the active peptide in the CT domain to be LLRVHK, active in the nanomolar range not only against PC2 but also PC1 [PUBMED:9756897, PUBMED:10812060]. Knock-out studies have shown that the PC2 nulls are not phenotypically equivalent to the 7B2 nulls, which suggests that 7B2 may have other activities in addition to being the activator of PC2 [PUBMED:12472887].

7B2 exhibits both structural and functional homology to proSAAS (INTERPRO), which is the PC1 binding protein. The CT domain of proSAAS contains the same inhibitor hexapeptide as 7B2, consequently both 7B2 and proSAAS are two members of a homologous family of prohormone convertase inhibitor proteins.

Gene Ontology

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Domain organisation

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  Seed
(12)
Full
(117)
Representative proteomes NCBI
(114)
Meta
(0)
RP15
(18)
RP35
(23)
RP55
(43)
RP75
(64)
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  Seed
(12)
Full
(117)
Representative proteomes NCBI
(114)
Meta
(0)
RP15
(18)
RP35
(23)
RP55
(43)
RP75
(64)
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

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Curation and family details

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Curation View help on the curation process

Seed source: Pfam-B_6776 (release 7.7)
Previous IDs: none
Type: Family
Author: Moxon SJ
Number in seed: 12
Number in full: 117
Average length of the domain: 200.70 aa
Average identity of full alignment: 45 %
Average coverage of the sequence by the domain: 85.95 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 44.7 38.8
Noise cut-off 20.1 22.0
Model length: 209
Family (HMM) version: 6
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