GLY67ARG substitution in RSPO4 disrupts the WNT signaling pathway due to an abnormal binding pattern with LGRs leading to anonychia
2017
R-Spondins regulate the WNT/β-
cateninsignaling pathway by interacting with
leucine rich-repeatcontaining G-protein coupled receptors (LGR4–6). These receptors share unique sequence and structural similarities with each other. Here, we report comparative binding analysis of R-Spondin-4 (RSPO4) with LGRs through structural characterization of a missense variant (GLY67ARG) identified in two
consanguineousfamilies of Pakistani origin. The modeled structure of RSPO4 comprises two contiguous
Furin-like cysteine-rich domains that are involved in binding with LGRs. We observed an overall conservation of overlapping interacting residues among LGRs which recognized RSPO4 at two specific parallel positions (sites ‘a’ and ‘b’). The residual contributions of RSPO4 reconciled previously defined interactions of
RSPO1with LGRs. To check the comparative expression pattern of β-
catenin, we quantified β-
cateninlevels in normal and
anonychiapatients. β-
cateninlevel was significantly reduced in the patients exhibiting mutated RSPO4 as compared to control individuals. These findings confirm that RSPO4 modulates the LGR-dependent WNT/β-
cateninsignaling pathway and may have therapeutic potential in
anonychiapatients.
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