Precursor processing

Precursors of insulin-like peptides contain signal peptides that are removed on entry into the endoplasmatic reticulum. Signal P 5.0 (Almagro Armenteros et al., 2019) was used online (http://www.cbs.dtu.dk/services/SignalP/) to predict where this cleavage would most likely occur. Some, but not all, precursors are further processed by convertases. Of these furin is ubiquitously present in all cell types and can thus potentially cleave any secreted protein with an appropriate cleavage site. Its consensus cleavage site is K/R-X-K/R-R; the two human IGF precursors are processed at KSAR and KSER, respectively (Humbel, 1990). Precursors that are produced in cells with a regulated pathway, such as neuroendocrine and enteroendocrine cells, are also exposed to other convertases like PC1/3 and PC2. Their consensus cleavages site is KR. However, effective proteolytic processing by convertases is strongly influenced by amino acid residues surrounding these consensus cleavage sites. For example, bulky residues immediately following the arginine residue, a proline residue before the consensus site, or disulfide bridges nearby can cause sufficient steric hindrance to inhibit cleavage. Using rules proposed to predict cleavage by PC1/3 and PC2 in both vertebrates and insects (Devi, 1991; Rholam et al., 1995; Veenstra, 2000), I have tried to indicate where the various precursors might be cleaved. It must be noted, however, that there is no certainty that these sites will be cleaved, nor can it be excluded that proteolytic processing occurs at sites that have not been indicated as such.