Sonic Hedgehog Shedding Results in Functional Activation of the Solubilized ProteinShow others and affiliations
2011 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 20, no 6, p. 764-774Article in journal (Refereed) Published
Abstract [en]
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.
Place, publisher, year, edition, pages
Elsevier, 2011. Vol. 20, no 6, p. 764-774
National Category
Molecular Biology
Identifiers
URN: urn:nbn:se:his:diva-25820DOI: 10.1016/j.devcel.2011.05.010ISI: 000291763500006PubMedID: 21664575Scopus ID: 2-s2.0-79958198050OAI: oai:DiVA.org:his-25820DiVA, id: diva2:1997252
Funder
German Research Foundation (DFG), GRK1549/1German Research Foundation (DFG), SFB 492-B15
Note
Elsevier user license. https://www.elsevier.com/about/policies-and-standards/open-access-licenses/elsevier-user
This work builds heavily on the information contained in PDB entry 3M1N. The authors of this entry, and the generous support of Biogen-IDEC in providing the file in advance of PDB deposition, are therefore gratefully acknowledged.This work was supported by DFG (German Research Council) grant SFB 492-B15, a Heinrich-Hertz fellowship (to K.G.), and DFG grant GRK1549/1. We also thank David J. Robbins (Dartmouth College) for Bosc23 cells and for his kind help in obtaining the human ShhN crystal coordinates, Ina Winkler and Anke Hahnenkamp (University of Münster) for cancer cell lines, and Jeffrey D.Esko (UCSD) for pgs-D677 cells. X-AC9 and 5E1 antibodies were obtained from the Developmental Studies Hybridoma Bank maintained by the University of Iowa. The excellent technical and organizational assistance of Sabine Kupich is gratefully acknowledged.
2025-09-112025-09-112025-11-12Bibliographically approved