Molecular evolution of PCSK family: Analysis of natural selection rate and gene loss.

Najmeh Parvaz,Zahra Jalali,Massimiliano Ruscica

doi:10.1371/journal.pone.0259085

Abstract

Proprotein convertases subtilisin kexins are serine endoproteases, playing critical roles in the biological functions, including lipid, glucose, and bile acid metabolism, as well as cell proliferation, migration, and metastasis. Experimental studies have demonstrated the physiological functions of PCSKs and their association with diseases; however, studies on the evolutionary history and diversification of these proteins are missing. In the present research, a bioinformatics study was conducted on the molecular evolution of several PCSKs family members and gene loss events across placental mammalian. In order to detect evolutionary constraints and positive selection, the CodeML program of the PAML package was used. The results showed the positive selection to occur in PCSK1, PCSK3, PCSK5, and PCSK7. A decelerated rate of evolution was observed in PCSK7, PCSK3, and MBTPS1 in Carnivores compared to the rest of phylogeny, and an accelerated evolution of PCSK1, PCSK7, and MBTPS1 in Muridae family of rodents was found. Additionally, our results indicated pcsk9 gene loss in 12 species comprising Carnivores and bats (Chiroptera). Future studies are required to evaluate the functional relevance and selective evolutionary advantages associated with these modifications in PCSK proteins during evolution.

Highlights

Proportion convertases subtilizing kexins (PCSKs) are Ca+2 dependent endoproteases belonging to the subtilizing family [1]
The results indicated conservation of the syntenic region, maintaining a similar composition in species with and without an intact PCSK9 gene, further supporting the PCSK9 gene loss suggested by our analysis in Bos taurus, Mustela putorius furo, Felis catus, Ursus maritimus, and Ovis aries (Fig 2B–2G, and S2 Table)
The results showed PCSK1, PCSK3, and PCSK5 to be the most closely related PCSK genes clustered into one clade with a high bootstrap value; whereas, PCSK9 and MBTPS1 were more distant to other PCSKs and constituted the periphery branches (Fig 6)

Summary

Introduction

Proportion convertases subtilizing kexins (PCSKs) are Ca+2 dependent endoproteases belonging to the subtilizing family [1]. These proteases play key roles in a series of biological functions, including lipid, glucose [2], and bile acid metabolism [3], as well as cell proliferation, migration, and metastasis, by converting inactive proteins into their mature forms [4, 5]. Nine members of the PCSK family are divided into two groups, named typical and atypical according to their cleavage site. PC1/3 (PCSK1), PC2 (PCSK2), furin (PCSK3), PC4 (PCSK4), PC5/6 (PCSK5), PACE4 (PCSK6), and PC7 (PCSK7) belong to the typical group, while MBTPS1 [PCSK8] and PCSK9 are members of the atypical group [6]. Furin, PCSK5, PCSK6, and PCSK7 are enzymes widely expressed and target a large number of substrates (e.g., plasma proteins, bacterial toxins, growth factors, and receptors) [2, 10]

Methods

Results

Conclusion