title: The evolutionary analysis reveals domain fusion of proteins with Frizzled-like CRD domain.
abstract: Frizzleds (FZDs) are transmembrane receptors in the Wnt signaling pathway and they play pivotal roles in developments. The Frizzled-like extracellular Cysteine-rich domain (Fz-CRD) has been identified in FZDs and other proteins. The origin and evolution of these proteins with Fz-CRD is the main interest of this study. We found that the Fz-CRD exists in FZD, SFRP, RTK, MFRP, CPZ, CORIN, COL18A1 and other proteins. Our systematic analysis revealed that the Fz-CRD domain might have originated in protists and then fused with the Frizzled-like seven-transmembrane domain (7TM) to form the FZD receptors, which duplicated and diversified into about 11 members in Vertebrates. The SFRPs and RTKs with the Fz-CRD were found in sponge and expanded in Vertebrates. Other proteins with Fz-CRD may have emerged during Vertebrate evolution through domain fusion. Moreover, we found a glycosylation site and several conserved motifs in FZDs, which may be related to Wnt interaction. Based on these results, we proposed a model showing that the domain fusion and expansion of Fz-CRD genes occurred in Metazoa and Vertebrates. Our study may help to pave the way for further research on the conservation and diversification of Wnt signaling functions during evolution.
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 430074, PR China; Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China; Department of Applied Physics, College of Information Science and Engineering, Shandong Agricultural University, Taian, Shandong, 271018, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Haibo
authors.initials: H
authors.lastname: Jia
authors.forename: Zhaowu
authors.initials: Z
authors.lastname: Ma
authors.forename: Huashan
authors.initials: H
authors.lastname: Ye
authors.forename: Mi
authors.initials: M
authors.lastname: Zhou
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
authors.forename: An-Yuan
authors.initials: AY
authors.lastname: Guo
mesh_terms: D000818:Animals; D003545:Cysteine / Q000235:genetics*; D019143:Evolution, Molecular; D005091:Exons; D051157:Frizzled Receptors / Q000235:genetics*; D006801:Humans; D007438:Introns; D010802:Phylogeny; D011993:Recombinant Fusion Proteins / Q000235:genetics*
chemical_list: D051157:Frizzled Receptors; D011993:Recombinant Fusion Proteins; D003545:Cysteine
keywords: 7TM; CPZ; CRD; Cysteine-rich domain; Domain fusion; Evolution; FZD; Frizzled; Frizzled-like CRD domain; Frizzled-like Cysteine-rich domain; Fz-CRD; G-protein-coupled receptor; GPCR; MFRP; MuSK; ROR; RTK; SFRP; Smo; Smoothened; TM; WGD; Wnt; carboxypeptidase Z; membrane Frizzled-related protein; muscle skeletal receptor tyrosine kinase; receptor tyrosine kinase; receptor tyrosine kinase-like orphan receptor; secreted Frizzled-related protein; seven-transmembrane domain; transmembrane domain; whole genome duplication