Abstract
R-spondin 4 is a secreted protein mainly associated with embryonic nail development. R-spondins have been recently identified as heparin-binding proteins with high affinity. Proteoglycan binding has been associated with both the TSR and the C terminal basic amino acid rich domains. In this paper, molecular modelling techniques were used to construct the model of R-spondin 4 TSR domain based on the structure of the F-spondin TSR domain 4 (30-40 cent sequence identity). Beside a positively charged surface in the TSR domain, presence of the basic amino acid rich domain which could forms a continuous heparin binding surface may explain the high affinity of R-spondins for heparin. Our results provide a framework for understanding the possible regulatory role of heparin in R-spondins signalling.
Highlights
R-spondin 4 gene plays a key role in the embryonic nail development
Structural analysis To create a model of R-spondin 4 TSR domain, we submitted the R-spondin 4 sequence to Protein Data Bank (PDB)-Blast, mGenTHREADER and PHYRE servers
The multiple sequence alignment (Figure 1) shows that the disulfide bond pattern within the TSR R-spondin 4 is the same as that found in F-spondin rather than that found in The disulfide bond pattern in group 1 (TSP-1)
Summary
Recent reports identified R-spondin 4 gene as responsible for congenital anonychia which is a rare autosomal-recessive disorder characterized by the absence of finger and toenails [1]. The human R-spondin 4 protein gene, member of R-spondin family (R-spondin 1-4), consists of five coding exons corresponding to predicted structural domains. Predicted domains include the Nterminal signal peptide sequences encoded by exon 1, the two adjacent cysteine rich furin like domains encoded by exon 2 and 3 and the single thrombospondin TSP1 domain that is encoded by exon 4. The two cysteine rich domains are thought to be responsible for binding to the wnt signalling pathway. The TSR domain has been identified within numerous protein families like complement factors, TRAP proteins of Plasmodium and Fspondin. TSR has been involved in the regulation of cell proliferation, migration and apoptosis in a variety of physiological and pathological settings, such as wound healing, inflammation and angiogenesis [4]
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