Abstract
BackgroundCholesterol homeostasis is maintained through finely tuned mechanisms regulating intestinal absorption, hepatic biosynthesis and secretion as well as plasma clearance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted enzyme of the serine protease family that reduces cellular uptake of plasma low-density lipoprotein (LDL) cholesterol by promoting LDL receptor (LDL-R) degradation. Species-specific positive selection has been noted in the LDLR promoter, leading to differential expression of LDLR among primates. Whether PCSK9 experienced significant selective pressure to maintain a functional relationship with its target protein, LDL-R, is unknown.Methodology/Principal FindingsWe compiled the sequences of the coding regions of PCSK9 from 14 primate species in the clade of Hominoids, Old World monkeys and New World monkeys. To detect selective pressure at the protein level, the ratios of nonsynonymous/synonymous substitution rate (d N/d S) under different evolutionary models were calculated across the phylogeny of PCSK9. Maximum likelihood analyses of d N/d S ratios for the aligned coding region sequences among 14 primate species indicated that PCSK9 was subject to a strong functional constraint (i.e., purifying selection). However, positive selection was noted in the functional carboxyl-terminal (C-terminal) domain in many branches across the phylogeny, especially in the lineage leading to the orangutan. Furthermore, at least five positively selected amino acids were detected in this lineage using the branch-site model A. In a sliding-window analysis, several d N/d S peaks in the C-terminal domain in both the human and the orangutan branches were noted.ConclusionsThese results suggest that among primates, differential selective pressure has shaped evolutionary patterns in the functional domains of PCSK9, an important regulator of cholesterol homeostasis.
Highlights
The low-density lipoprotein (LDL) receptor gene (LDLR) plays a key role in cholesterol homeostasis by receptor-mediated endocytosis of LDL cholesterol
We aimed to address three questions: 1) whether the ratio of nonsynonymous and synonymous evolutionary rate of Proprotein convertase subtilisin/kexin type 9 (PCSK9) varied significantly among various primate lineages, 2) whether there is an episodic adaptive evolution of PCSK9 in primates, and 3) which, of any, amino acids of PCSK9 were under positive selection
The main finding of our study is that there is evidence for functional constraint in the coding sequences of PCSK9 through primate evolution
Summary
The low-density lipoprotein (LDL) receptor gene (LDLR) plays a key role in cholesterol homeostasis by receptor-mediated endocytosis of LDL cholesterol. Proprotein convertase subtilisin/kexin type 9 (PCSK9, MIM 607786) – a secreted enzyme of the serine protease family – is a newly discovered regulator of LDLR [1,2,3]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted enzyme of the serine protease family that reduces cellular uptake of plasma low-density lipoprotein (LDL) cholesterol by promoting LDL receptor (LDL-R) degradation. Maximum likelihood analyses of dN/dS ratios for the aligned coding region sequences among 14 primate species indicated that PCSK9 was subject to a strong functional constraint (i.e., purifying selection). Positive selection was noted in the functional carboxyl-terminal (C-terminal) domain in many branches across the phylogeny, especially in the lineage leading to the orangutan. These results suggest that among primates, differential selective pressure has shaped evolutionary patterns in the functional domains of PCSK9, an important regulator of cholesterol homeostasis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
