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HGNC Approved Gene Symbol: PCSK1N
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38) : X:48,831,096-48,835,610 (from NCBI)
Most neuroendocrine peptides are initially synthesized as larger precursors that require proteolytic processing to generate the bioactive moiety. Prohormone convertase-1 (PC1, or PCSK1; 162150) mediates the proteolytic cleavage of neuroendocrine peptide precursors, and PCSK1N is an inhibitor of PCSK1 activity.
Fricker et al. (2000) identified PCSK1N, which they called proSAAS, as a protein highly enriched in the brains of mice homozygous for an inactive allele of the neuropeptide-processing enzyme carboxypeptidase E (CPE; 114855). Database analysis followed by PCR using brain cDNA led to the cloning of mouse, rat, and human PCSK1N. The deduced 260-amino acid human sequence contains a 33-amino acid N-terminal signal sequence as well as endoprotease-processing sites. Overall sequence conservation between the human and rodent sequences is about 84%. Northern blot analysis of multiple human tissues revealed strong expression of a 1.2-kb transcript in all brain regions tested and in pancreas. Low but detectable expression was found in kidney, and no expression was found in heart, placenta, lung, liver, and skeletal muscle. In situ hybridization of adult rat tissues showed expression limited to neurons in every major structural region of the brain and in the spinal cord. Expression was also found in adrenal medulla and in the anterior and intermediate lobes of the pituitary. Immunolocalization of rat Pcsk1n transfected into mouse pituitary corticotrophs indicated a perinuclear distribution similar to the distribution of trans-Golgi markers. Immunoreactivity was also detected in the tips of the corticotrophs, consistent with localization within mature secretory vesicles. Rat Pcsk1n transfected into mouse pituitary corticotrophs was secreted into the medium as a 4-kD C-terminal fragment and a 22-kD N-terminal fragment, as well as the intact 26-kD protein.
Fricker et al. (2000) showed that overexpression of rat Pcsk1n led to reduced processing of proopiomelanocortin (POMC; 176830). Using the recombinant protein in in vitro assays, they found that Pcsk1n could inhibit PC1 but not PC2 (162151), and kinetic analysis indicated that Pcsk1n is either a noncompetitive inhibitor of PC1 or a tight-binding competitive inhibitor with a slow off rate.
Fortenberry et al. (2002) confirmed that mouse Pcsk1n inhibits PC1. Using a truncation mutant, they localized the inhibitory domain to the first 24 residues of the C-terminal peptide.
Using in vitro and in vivo analyses, Gomes et al. (2013) showed that Gpr171 (618925) was a receptor for the Prosaas-derived neuropeptide BigLEN (LENSSPQAPARRLLPP) in both mouse hypothalamus and Neuro2A cells. The C-terminal region of BigLEN bound to Gpr171, and the 4 C-terminal residues of BigLEN were necessary and sufficient to activate Gpr171. Knockdown of Gpr171 in mice affected feeding behavior and metabolism, indicating that Gpr171 and BigLEN play a major role in regulating these responses.
By genomic Southern analysis using a radiation hybrid panel, Fricker et al. (2000) mapped the PCSK1N gene to chromosome Xp11.3.
Fortenberry, Y., Hwang, J.-R., Apletalina, E. V., Lindberg, I. Functional characterization of proSAAS: similarities and differences with 7B2. J. Biol. Chem. 277: 5175-5186, 2002. [PubMed: 11719503] [Full Text: https://doi.org/10.1074/jbc.M104531200]
Fricker, L. D., McKinzie, A. A., Sun, J., Curran, E., Qian, Y., Yan, L., Patterson, S. D., Courchesne, P. L., Richards, B., Levin, N., Mzhavia, N., Devi, L. A., Douglass, J. Identification and characterization of proSAAS, a granin-like neuroendocrine peptide precursor that inhibits prohormone processing. J. Neurosci. 20: 639-648, 2000. [PubMed: 10632593] [Full Text: https://doi.org/10.1523/JNEUROSCI.20-02-00639.2000]
Gomes, I., Aryal, D. K., Wardman, J. H., Gupta, A., Gagnidze, K., Rodriguiz, R. M., Kumar, S., Wetsel, W. C., Pintar, J. E., Fricker, L. D., Devi, L. A. GPR171 is hypothalamic G protein-coupled receptor for BigLEN, a neuropeptide involved in feeding. Proc. Nat. Acad. Sci. 110: 16211-16216, 2013. [PubMed: 24043826] [Full Text: https://doi.org/10.1073/pnas.1312938110]