Figure 1.
Schematic overview of the Hedgehog signaling pathway.
Signal-secreting cells (left) release the morphogen protein Hh after modifying it through the addition of two lipid molecules. A C-terminal cholesterol moiety is added via the activity of an intein domain within Hh itself, whereas the protein Ski/Rasp attaches an N-terminal palmitic acid. Lipid-modified Hh is released from the producing cell with the aid of the Disp protein. Signal-receiving cells (right) bind Hh via the transmembrane protein Ptc, perhaps with the assistance of the iHog/Boi family of proteins. Hh binding to Ptc leads to the de-repression of the GPCR-related protein Smo. Smo subsequently initiates intracellular signal transduction events, which involve proteins such as Cos2, Fu, and Su(fu), that lead to changes in target gene expression. The inhibition of Smo by Ptc is of particular interest here; it occurs nonstoichiometrically, in a manner that appears to rely on a catalytic activity in Ptc.
Figure 2.
Ptc and Disp, two key proteins the Hh pathway, in their evolutionary context.
(A) A phylogenetic tree of proteins related to Patched, limited to proteins that are full-length (i.e., those that contain all 12 transmembrane segments), is shown. The tree is color-coded according to the taxonomy of the organisms in which the respective proteins are found. Note one particular family of deeply branching bacterial Ptc homologs, the HpnN family, which encodes a transporter that is predicted to be associated with hopanoid biosynthesis. (B) A typical hopanoid is shown, next to cholesterol, a typical sterol. (C) Sequence alignment of selected HpnN family members with the most common reciprocal-best-match, the Disp family, is shown. Only six sequences are shown (three bacterial and three eukaryotic proteins); the alignment is restricted to transmembrane segments 2 to 6, which form the so-called SSD. (D) and (E) Evidence is shown for a functional association between HpnN-family transporters and HpnF; the latter being the enzyme that catalyzes the first step of hopanoid biosynthesis. Both genes tend to be either present or absent together in a given genome in proteobacteria and occasionally occur in direct chromosomal proximity.
Figure 3.
A parsimonious scenario for the evolution of the Ptc/Smo system.
We hypothesize that during the transition to multicellularity, a pre-existing lipid homeostasis system took on a new function in signaling. Initially, an ancient lipid transporter diversified; one of its descendents came under the transcriptional control of a GPCR that sensed the same lipid (i.e., forming a negative homeostatic feedback loop). Then, the fortuitous addition of a protein moiety to the lipid in question brought the system under the control of gene expression; a neighboring cell could now secrete the lipid at will (by coupling it to the protein moiety). Because the combined lipid–protein molecule would block the transporter, this meant that the sending cell was capable of changing the perceived homeostatic state of the receiving cell, which would have established a graded (quantitative) mode of cell–cell communication.