Contents |
The phenomenon of prohormone conversion was discovered by Donald F. Steiner while examining the biosynthesis of insulin in 1967.[1] At the same time, while conducting chemical sequencing of β-lipotrophic hormone (βLPH) with sheep pituitary glands Dr. Michel Chretien determined that the sequence of another hormone, Melanocyte-stimulating hormone ( βMSH).[2] This was the chemical evidence, at the level of primary protein sequence that peptide hormones could be found within larger protein molecules. The identity of the responsible enzymes was not clear for decades. In 1984, David Julius, working in the laboratory of Jeremy Thorner, identified the product of the Kex2 gene as responsible for processing of the alpha factor mating pheromone. Robert Fuller, working with Thorner, identified the partial sequence of the Kex2-homologous Furin gene in 1989. In 1990 human Kex2-homologous genes were cloned by the Steiner group, Nabil Seidah and co-workers, Wim J.M. van de Ven and co-workers, Yukio Ikehara and co-workers, Randal Kaufman and co-workers, Gary Thomas and co-workers, and Kazuhisa Nakayama and co-workers.
One of the most well-known PPCs is Furin. Some of its substrates are: proparathyroid hormone, transforming growth factor beta 1 precursor, proalbumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, beta subunit of pro-nerve growth factor and von Willebrand factor. A furin-like pro-protein convertase has been implicated in the processing of RGMc (also called hemojuvelin hemojuvelin). Both the Ganz and Rotwein groups demonstrated that furin-like proprotein convertases (PPC) are responsible for conversion of 50 kDa HJV to a 40 kDa protein with a truncated COOH-terminus, at a conserved polybasic RNRR site. This suggests a potential mechanism to generate the soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans.[3][4]
Kex2 was first purified and characterized by Charles Brenner and Robert Fuller in 1992. The Kex2 crystal structure was solved by a group led by Dagmar Ringe, Robert Fuller and Gregory Petsko. That of Furin was determined by a group led by Manual Than and Wolfram Bode. The key features of Kex2 and Furin are a subtilisin-related catalytic domain, a specificity pocket that requires the amino acid amino terminal to the scissile bond to be arginine for rapid acylation, and a P-domain carboxy-terminal to the subtilisin domain, which is required for biosynthesis.
To date there are 9 PCSKs with varying functions and tissue distributions.[5] Often, due to similar times of discovery from different groups the same PCSKs have acquired multiple names. In an attempt to alleviate confusion, there is a trend towards using the PCSK prefix with the appropriate number suffix.[6]
| current PCSK nomenclature | Other common names |
|---|---|
| PCSK1 | PC1, PC3 (new name: PC1/3) |
| PCSK2 | PC2 |
| PCSK3 | Furin, Pace, PC1 |
| PCSK4 | PC4 |
| PCSK5 | PC5, PC6 new name:PC5/6 |
| PCSK6 | PACE4 |
| PCSK7 | PC7, PC8 |
| PCSK8 | Site 1 Protease, S1P,SKI |
| PCSK9 | NARC-1 |