title: Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain.
abstract: Autocatalytic processing mediated by the carboxyterminal domain of the hedgehog (hh) protein precursor (Hh) generates an amino-terminal product that accounts for all known signaling activity. The role of autoprocessing biogenesis of the hh signal has been unclear, since a truncated unprocessed protein lacking all carboxy-terminal domain sequences retains signaling activity. Here, we present evidence that the autoprocessing reaction proceeds via an internal thioester intermediate and results in a covalent modification that increases the hydrophobic character of the signaling domain and influences its spatial and subcellular distribution. We demonstrate that truncated unprocessed amino-terminal protein causes embryonic mispatterning, even when expression is localized to cells that normally express Hh, thus suggesting a role for autoprocessing in spatial regulation of hh signaling. This type of processing also appears to operate in the biogenesis of other novel secreted proteins.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Porter
authors.forename: S C
authors.initials: SC
authors.lastname: Ekker
authors.forename: W J
authors.initials: WJ
authors.lastname: Park
authors.forename: D P
authors.initials: DP
authors.lastname: von Kessler
authors.forename: K E
authors.initials: KE
authors.lastname: Young
authors.forename: C H
authors.initials: CH
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.forename: A S
authors.initials: AS
authors.lastname: Woods
authors.forename: R J
authors.initials: RJ
authors.lastname: Cotter
authors.forename: E V
authors.initials: EV
authors.lastname: Koonin
authors.forename: P A
authors.initials: PA
authors.lastname: Beachy
mesh_terms: D000818:Animals; D002478:Cells, Cultured / Q000502:physiology; D016384:Consensus Sequence; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins; D004952:Esters / Q000737:chemistry; D053823:Hedgehog Proteins; D008055:Lipids / Q000737:chemistry; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D029721:Drosophila Proteins; D004952:Esters; D053823:Hedgehog Proteins; D008055:Lipids; D011506:Proteins; D013438:Sulfhydryl Compounds; D014867:Water; C077245:hh protein, Drosophila