Abstract
Leucine-rich repeat-containing G protein-coupled
receptors 4–6 (LGR4–LGR6) are receptors for
R-spondins, potent Wnt agonists that exert profound
trophic effects on Wnt-driven stem cells compartments.
We present crystal structures of a
signaling-competent fragment of R-spondin 1
(Rspo1) at a resolution of 2.0 A°
and its complex
with the LGR5 ectodomain at a resolution of 3.2 A°
.
Ecto-LGR5 binds Rspo1 at its concave leucinerich-
repeat (LRR) surface, forming a dimeric 2:2
complex. Fully conserved residues on LGR4–LGR6
explain promiscuous binding of R-spondins. A
phenylalanine clamp formed by Rspo1 Phe106 and
Phe110 pinches Ala190 of LGR5 and is critical for
binding. Mutations related to congenital anonychia
reduce signaling, but not binding of Rspo1 to
LGR5. Furthermore, antibody binding to the
extended loop of the C-terminal LRR cap of LGR5
activates signaling in a ligand-independent manner.
Thus, our data reveal binding of R-spondins to
conserved sites on LGR4–LGR6 and, in analogy to
FSHR and related receptors, suggest a direct
signaling role for LGR4–LGR6 in addition to its formation
of Wnt receptor and coreceptor complexes.
Original language | English |
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Pages (from-to) | 1885-1892 |
Number of pages | 8 |
Journal | Cell Reports [E] |
Volume | 3 |
Issue number | 6 |
DOIs | |
Publication status | Published - 2013 |