Sonic Hedgehog Shedding Results in Functional Activation of the Solubilized Protein

• DOI: 10.1016/j.devcel.2011.05.010
• Publication Date: 2011-06-21T19:25:41Z
• Authors: Stefanie Ohlig; Pershang Farshi; Ute Pickhinke; Johannes van den ...; Susanne Höing; Stanislav Jakuschev; Daniel Hoffmann; Rita Dreier; Hans R. Schöler; Tabea Dierker; Christian Bordych; Kay Grobe
• Keywords: Models, Molecular; Patched Receptors; 0303 health sciences; Protein Conformation; Palmitates; Antibodies, Monoclonal; Cell Differentiation; Receptors, Cell Surface; Chick Embryo; Crystallography, X-Ray; Peptide Fragments; Recombinant Proteins; Patched-1 Receptor; Mice; 03 medical and health sciences; Chondrocytes; NIH 3T3 Cells; Animals; Humans; Hedgehog Proteins; Biologie; Protein Processing, Post-Translational; Cells, Cultured; Developmental Biology

All Hedgehog (Hh) proteins are released from producing cells despite being synthesized as N- and C-terminally lipidated, membrane-tethered molecules. Thus, a cellular mechanism is needed for Hh solubilization. We previously suggested that a disintegrin and metalloprotease (ADAM)-mediated shedding of Sonic hedgehog (ShhNp) from its lipidated N and C termini results in protein solubilization. This finding, however, seemed at odds with the established role of N-terminal palmitoylation for ShhNp signaling activity. We now resolve this paradox by showing that N-palmitoylation of ShhNp N-terminal peptides is required for their proteolytic removal during solubilization. These peptides otherwise block ShhNp zinc coordination sites required for ShhNp binding to its receptor Patched (Ptc), explaining the essential yet indirect role of N-palmitoylation for ShhNp function. We suggest a functional model in which membrane-tethered multimeric ShhNp is at least partially autoinhibited in trans but is processed into fully active, soluble multimers upon palmitoylation-dependent cleavage of inhibitory N-terminal peptides.