title: Evolution of the class C GPCR Venus flytrap modules involved positive selected functional divergence.
abstract: BACKGROUND
  Class C G protein-coupled receptors (GPCRs) represent a distinct group of the GPCR family, which structurally possess a characteristically distinct extracellular domain inclusive of the Venus flytrap module (VFTM). The VFTMs of the class C GPCRs is responsible for ligand recognition and binding, and share sequence similarity with bacterial periplasmic amino acid binding proteins (PBPs). An extensive phylogenetic investigation of the VFTMs was conducted by analyzing for functional divergence and testing for positive selection for five typical groups of the class C GPCRs. The altered selective constraints were determined to identify the sites that had undergone functional divergence via positive selection. In order to structurally demonstrate the pattern changes during the evolutionary process, three-dimensional (3D) structures of the GPCR VFTMs were modelled and reconstructed from ancestral VFTMs.
  
  
  RESULTS
  Our results show that the altered selective constraints in the VFTMs of class C GPCRs are statistically significant. This implies that functional divergence played a key role in characterizing the functions of the VFTMs after gene duplication events. Meanwhile, positive selection is involved in the evolutionary process and drove the functional divergence of the VFTMs. Our results also reveal that three continuous duplication events occurred in order to shape the evolutionary topology of class C GPCRs. The five groups of the class C GPCRs have essentially different sites involved in functional divergence, which would have shaped the specific structures and functions of the VFTMs.
  
  
  CONCLUSIONS
  Taken together, our results show that functional divergence involved positive selection and is partially responsible for the evolutionary patterns of the class C GPCR VFTMs. The sites involved in functional divergence will provide more clues and candidates for further research on structural-function relationships of these modules as well as shedding light on the activation mechanism of the class C GPCRs.
authors.affiliation: Key laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, PR China. jhcao@mail.hzau.edu.cn
authors.forename: Jianhua
authors.initials: J
authors.lastname: Cao
authors.forename: Siluo
authors.initials: S
authors.lastname: Huang
authors.forename: Ji
authors.initials: J
authors.lastname: Qian
authors.forename: Jinlin
authors.initials: J
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Zhixi
authors.initials: Z
authors.lastname: Su
authors.forename: Ji
authors.initials: J
authors.lastname: Yang
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu