Figure 5. Simplified model for the conversion of membrane-bound Hh into soluble clusters.

Surface-tethered wild-type Hh monomers (colored green and blue for clarity) form multimeric clusters with their extended N- and C-terminal lipidated peptides tethered to the cell membrane. (a) Membrane-proximal proteolytic processing (scissors) removes lipidated membrane anchors and releases Hh clusters from posterior cells. As a consequence, protein concentrations at any position in the responsive (anterior) field correlate with their biological activities (their Ptc-receptor-binding capacities). Because partially processed clusters are not released, the role of both lipids at this point is to control quantitative Hh processing and bioactivation. (b) Unpalmitoylated Hh^C85S only requires processing of its cholesterylated C-terminus for release: As a consequence, a fraction of wild-type Hh in mixed clusters has its Ptc-receptor-binding sites and bioactivity blocked (indicated by the X) by unprocessed adjacent Hh^C85S N-termini (asterisk). Signaling at any position in the field is thus reduced, leading to dominant negative wing phenotypes (right). LOF: loss of function. (c) Artificial truncation of unpalmitoylated Hh^C85S N-termini restores wild-type Hh function. wt: wild type.