title: Sonic hedgehog shedding results in functional activation of the solubilized protein.
abstract: 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.
authors.affiliation: Institute for Physiological Chemistry and Pathobiochemistry, University Hospital Münster, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Ohlig
authors.forename: Pershang
authors.initials: P
authors.lastname: Farshi
authors.forename: Ute
authors.initials: U
authors.lastname: Pickhinke
authors.forename: Johannes
authors.initials: J
authors.lastname: van den Boom
authors.forename: Susanne
authors.initials: S
authors.lastname: Höing
authors.forename: Stanislav
authors.initials: S
authors.lastname: Jakuschev
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoffmann
authors.forename: Rita
authors.initials: R
authors.lastname: Dreier
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler
authors.forename: Tabea
authors.initials: T
authors.lastname: Dierker
authors.forename: Christian
authors.initials: C
authors.lastname: Bordych
authors.forename: Kay
authors.initials: K
authors.lastname: Grobe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D002642:Chick Embryo; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D018360:Crystallography, X-Ray; D053823:Hedgehog Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D010168:Palmitates / Q000494:pharmacology*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D053823:Hedgehog Proteins; D010168:Palmitates; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010446:Peptide Fragments; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins