The PCSK1 gene is located on chromosome 5q15-21 in humans, and chromosome 13c in the mouse (Seidah NG et al. 1991a, Seidah NG et al. 1991b). The promoter of this gene contains cAMP-response elements (CRE-1 and CRE-2). Transcription factors such as cAMP-responsive element-binding protein 1 ( CREB1) and Activating Transcription Factor 1 ( ATF1) that can transactivate the PCSK1 promoter (Jansen E et al, 1997, Espinosa VP et al, 2008).

The DNA sequence of PCSK1contains 14 exons and the transcript length of 5068 bps is translated to a 753 residues protein. 4 spliced variants of PCSK1 are identified (splice variants) that code for 3 protein isoforms of 753 aa, 706 aa and 157 aa in length, respectively (M_000439, NM_001177875).

PCSK1 is the third member of the proprotein convertase Subtilisin/Kexin-like family that was cloned from mammalian organisms, after furin and PC2 (Seidah NG et al. 1991, Smeekens SP et al, 1991, reviewed in Scamuffa N et al, 2006). The domain structure of PCSK1 precursor consists of four domains that include a prodomain (or prosegment), a catalytic domain, a P domain, and a carboxy-terminal domain (Figure 2). The propeptide domain is essential for the appropriate protein folding and exit from the endoplasmic reticulum (ER) of PCSK1 (Creemers JW1 et al, 1995). The catalytic domain is highly conserved among various species. Similar to the other members of the subtilisin superfamily the amino acids Asp, His, and Ser form the catalytic triad. The P domain presents a key role in the regulation of the PCSK1 activity through calcium and pH modulation (Zhou A1 et al, 1998). The carboxy-terminal domain is mainly involved in PCSK1 sorting into secretory granules (Dikeakos JD et al. 2009).
After the production of PCSK1 preproform in the endoplasmic reticulum and removal of its signal peptide, the 94kDa precursor of PCSK1 activation occurs after both N-and C-terminal domains cleavages. The 94kDa precursor undergoes an initial autocatalytic processing of its prosegment (prodomain). After protein scaffold and N-glycosylation, proPCSK1 exits the ER and sorts to the trans-Golgi network. In the early compartment, proPCSK1 is sulfated on its sugar residues. Lately during progression to the mildly acidic environment, an autocatalytic cleavage occurs to remove the prodomain and generates a 87kDa active PCSK1 form (reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016). The cleavage of proPCSK1 that generates the 87 kDa PCSK1 is calcium-independent and occurs at a neutral pH. PCSK1 is sorted after to immature secretory granules where is activated by a cleavages at the C-terminal area and generates the 74 and 66kDa active forms. The active forms are than accumulated in dense-core secretory granules prior secretion.

PCSK1 is expressed in the neuroendocrine system such as brain, adrenal glands and in endocrine cells of the small intestine (reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016). Weak expression of PCSK1 is detected in adipocytes, α-cells of the pancreatic islets and certain types of immune cells. In brain, PC1 is mainly expressed in the hypothalamus (Dong W et al , 1997), but it is also found in cerebral cortex (Figure 3), hippocampus, and cerebellum (Billova S1, ET AL , 2007, Schäfer MK1, et al 1993). PC1/3 is also expressed in the adrenal medulla, pituitary, thyroid gland (Scopsi L et al. 1995, Day R ET AL 1992), endocrine pancreas (β-cells), liver and small intestine; including L and K cells (Tanaka S ET AL 1996). At low levels, PC1/3 was also detected in adipocytes (Min SYet al, 2016), in pancreatic islets (Itoh Y1, et al 1996), and in certain types of immune cells (LaMendolaet al 1997, Vindrola O et al 1994).

In neuroendocrine cells, PCSK1 is mainly localized to the secretion granules and traffics within the regulated secretory pathway (Hornby PJ et al 1993, Malide D et al 1995). In macrophages PC1/3 is retained at the TGN as a pool that traffics to LAMP- related vesicles. PC1 vesicules are mostly detected during macrophages activation (Gagnon H et al, 2013)

PCSK1 cleaves protein precursors at the consensus motif (K/R)-Xn-(K/R)↓, with n=0, 2, 4 or 6, and X=any amino acids except Cys, to release mature proteins. PCSK1 favors cleavage after K/R motif, but is also able to cleave after other dibasic residues. PCSK1 often collaborates with PCSK2 to cleave substrates, such as neuropeptides and peptide hormones and its activity can be inhibited by the endogenous inhibitor proSAAS. PC1/3 gene disruption results in various developmental abnormalities (reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016) and PC1/3 null mice exhibit growth retardation (reviewed in Scamuffa N et al, 2006). The adult mutant mice are 60% of the normal size and show similarities with mice having mutant growth hormone releasing hormone ( GHRH) receptor ( GHRHR). Further analysis indicated that insulin-like growth factor-1 ( IGF1) and GHRH levels were significantly decreased in these mice; that may explain the observed growth retardation. PCSK1 null mice process normally pituitary POMC to ACTH and have normal levels of blood corticosterone. Like PCSK2 null mice, PCSK1 null mice also develop hyperproinsulinemia. These mice maintain normal glucose (Glc) tolerance in response to injection of glucose, suggesting that their hyperproinsulinemia does not impair their glucose homeostasis. Previously, Jackson et al. (reviewed in Scamuffa N et al, 2006) reported a human case of PC1/3 deficiency. The latter is due to PCSK1 gene mutation that prevents activation and secretion of proPC1/3 from the endoplasmic reticulum. The patient showed neonatal obesity. Subsequent studies revealed the presence of various endocrine defects, including the presence of very high circulating levels of proinsulin and multiple forms of partially processed POMC [ACTH precursors intermediate], low-serum estradiol, follicle-stimulating hormone, and LH. In 2003, another PCSK1 deficiency female subject was reported. In addition to the shared phenotypes with the previous subject, this female infant presented severe diarrhea, which started on the third postnatal day. Metabolic studies revealed a defect in the absorption of monosaccharides and fat, revealing the role of PC1/3 in the small intestinal absorptive function. Although the phenotypes of the PCSK1 null mice differ from those observed in these patients (PCSK1 null mice are not obese), the findings confirmed the importance of PCSK1 as a key neuroendocrine convertase (reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016).

An important paralog of this gene is PCSK2. Analysis of PCSK1 structure revealed that PCSK1 catalytic domain present a low percentage of homology with those of the other PCs (only 39% between PCSK1 and FURIN). The PCSK1 prodomain is formed by 83 residues and is highly conserved between orthologs (∼80% of sequence identity), although is not well conserved among paralogs of the convertase family (∼30-40%). The catalytic domain of PC1/3 is formed by 343 residues and is the most conserved region among proproteine convertases family members, with 50-60% sequence similarity. The P domain is a well-conserved region in PCs of approximately 150 residues and the Arg⁵²⁶-Arg-Gly-Asp⁵²⁹ (RRGD motif) is crucial for proper proPC1/3 processing and sorting to the secretory granules (reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016). The C-terminus of PCSK1 with 159 aa is involved in the sorting processes to the dense core secretory granules, as well as in PCSK1 activity and stability ((reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016).

Various mutations were reported for human PCSK1 gene and were associated with various syndromes including obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels (reviewed in Ramos-Molina B et al , 2016 and Stijnen P et al 2016).