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PACE4 was the fourth of the human prohormone convertase enzymes to be discovered, after furin, PC1 and PC2. Like furin, PC1 and PC2, PACE4 is a serine proteinase that cleaves after pairs of basic amino acids, but with some differences in substrate specificity and distribution. The catalytic domain has homology to other PACE enzymes, the prohormone convertase family initially discovered for their role in processing POMC, insulin and other prohormones, and later found to process a wider range of precursor proteins. Some have renamed the prohormone convertases as proprotein convertases, and another group has renamed the entire family with a uniform nomenclature of SPCs (s ubtilisin-like p roprotein c onvertases), with PACE4 getting the SPC4 moniker. PACE4 structure contains a propeptide domain, a catalytic domain and an RGD containing cystein-rich domain (homo-b). The PCs have an RxxR consensus cleavage requirement, and the propeptide is separated from the mature protein by just such a sequence. After cleavage of the propeptide domain, PACE4 becomes a two-chain form, and the propeptide piece is released after a second internal cleavage. Unlike furin, which resides mainly in the TGN and is cycled to the surface, much of PACE4 is a secreted proteinase. PACE4 is expressed at low levels in most tissues, but found in highest concentration in the anterior pituitary, controlled in part by thyroid hormone levels. Other tissues expressing PACE4 include cerebellum, pancreatic islet cells, liver and kidneys, spleen, thymus, and gut. Overexpression of PACE4 accelerates tumor growth in cancer models, and blocking PACE4 decreases tumor growth. PACE4 cleaves a wide variety of proteins, including growth factors, viral coat proteins, matrix metalloproteinases, mostly activating latent forms of the proteins. A number of splice variants have been reported for PACE4, one with a later start site, and the rest with truncations in the cysteine-rich carboxyterminal area. The longest form (PACE4-G) encodes a 975 amino acid protein with a predicted mass of 106.63 kDa, and a pI of 8.83, but glycosylation and other post-translational modifications make the pre-pro PACE4 run at 115-122 kDa, the mature PACE4 at 106 kDa, and processed PACE4 at 66 kDa. The splice variants (PACE4A-I) sequence's encode proteins of 969, 962, 956, 664, 652, 623, 497, and 487 amino acids, with predicted masses of 106.4, 105.3, 105.1, 73.0, 71.8, 68.2, 54.92 and 53.0 kDa and pIs of 8.73, 8.83, 8.73, 8.82, 8.7, 9.02, 6.22 and 9.2 respectively. Only the longest 3-4 species are thought to be proteolytically active, and it remains unclear how abundant the splice variants are or their functions.
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Western blot - PACE4 antibody (ab58226)