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Abstract
<p class="first" id="P1">The Hedgehog (Hh) pathway plays a central role in the development
of multicellular
organisms, guiding cell differentiation, proliferation and survival. While many components
of the vertebrate pathway were discovered two decades ago, the mechanism by which
the Hh signal is transmitted across the plasma membrane remains mysterious. This fundamental
task in signalling is carried out by Smoothened (SMO), a human oncoprotein and validated
cancer drug target that is a member of the G-protein coupled receptor protein family.
Recent structural and functional studies have advanced our mechanistic understanding
of SMO activation, revealing its unique regulation by two separable but allosterically-linked
ligand-binding sites. Unexpectedly, these studies have nominated cellular cholesterol
as having an instructive role in SMO signalling.
</p>