Molecular evolutionary and structural analysis of familial exudative vitreoretinopathy associated FZD4 gene

Abstract

Background Frizzled family members belong to G-protein coupled receptors and encode proteins accountable for cell signal transduction, cell proliferation and cell death. Members of Frizzled receptor family are considered to have critical roles in causing various forms of cancer, cardiac hypertrophy, familial exudative vitreoretinopathy (FEVR) and schizophrenia. Results This study investigates the evolutionary and structural aspects of Frizzled receptors, with particular focus on FEVR associated FZD4 gene. The phylogenetic tree topology suggests the diversification of Frizzled receptors at the root of metazoans history. Moreover, comparative structural data reveals that FEVR associated missense mutations in FZD4 effect the common protein region (amino acids 495–537) through a well-known phenomenon called epistasis. This critical protein region is present at the carboxyl-terminal domain and encompasses the K-T/S-XXX-W, a PDZ binding motif and S/T-X-V PDZ recognition motif. Conclusion Taken together these results demonstrate that during the course of evolution, FZD4 has acquired new functions or epistasis via complex patter of gene duplications, sequence divergence and conformational remodeling. In particular, amino acids 495–537 at the C-terminus region of FZD4 protein might be crucial in its normal function and/or pathophysiology. This critical region of FZD4 protein may offer opportunities for the development of novel therapeutics approaches for human retinal vascular disease. Electronic supplementary material The online version of this article (10.1186/s12862-019-1400-9) contains supplementary material, which is available to authorized users.

FZD4 in a Large Chinese Population With Familial Exudative Vitreoretinopathy: Molecular Characteristics and Clinical Manifestations

“… 30 The region of amino acids 495 to 537 is deemed critical with respect to its structure, function, and involvement in FEVR. 31 The amino acids belonging to both the transmembrane domain 7 group and the amino acids 495 to 537 group were assigned to the latter group. Of the 51 mutations detected in this study, 22 were found in CRD, 17 in transmembrane domain 7, there were 3 in amino acids 495 to 537 at the C-terminus region, and 6 in others (see Fig.…”

Ocular phenotype and genetical analysis in patients with retinopathy of prematurity

“…The CRD belongs to the extracellular region of FZD4 protein, and is found to be responsible for Norrin/β-catenin signaling pathway, as Norrin specifically binds to the CRD of FZD4 but not to CRDs of other 14 mammalian Frizzled or secreted Frizzled-related proteins [ 20 ], the mutational effects on CRD have been verified by altered cellular processing, plasma membrane targeting, interaction with Norrin ligand, and the ability to activate the signaling pathway [ 21 ]. The TMD is conserved among all the putative paralogs of the frizzled receptor family [ 22 ], and contains seven transmembrane α-helices [ 23 ]; The carboxyl-terminal region possesses a conserved K-T/S-XXX-W PDZ-binding motif that locates immediately after the hydrophobic TMD, this motif is necessary for canonical Wnt pathway initiation and Disheveled (Dvl) protein phosphorylation, and interaction of FZD4 with Dvl completely diminishes while the motif encountering any mutation [ 24 ]. The amino-terminal membrane localizing signal peptide sequence is rich in hydrophobic residues, and is known to translocate FZD4 to the plasma membrane, mutations that occur in this region might result in impaired stability of FZD4 protein and its mistranslocation subsequently [ 25 ].…”

Molecular evolutionary and structural analysis of human UCHL1 gene demonstrates the relevant role of intragenic epistasis in Parkinson’s disease and other neurological disorders

“…The putative orthologous protein sequences of human UCHL1 were retrieved from protein databases accessible at Ensemble [ 50 ] and National Center for Biotechnology Information [ 51 ] by using BLAST p bidirectional best hit approach [ 52 ]. Further confirmation of the common ancestry of the putative orthologs was obtained by clustering homologous proteins within phylogenetic trees [ 53 , 54 ]. Sequences whose position within a tree is in sharp conflict with the uncontested animal phylogeny are excluded from the analysis.…”