Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain.
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.
Porter
J A
JA
Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
Ekker
S C
SC
Park
W J
WJ
von Kessler
D P
DP
Young
K E
KE
Chen
C H
CH
Ma
Y
Y
Woods
A S
AS
Cotter
R J
RJ
Koonin
E V
EV
Beachy
P A
PA
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
D029721:Drosophila Proteins; D004952:Esters; D053823:Hedgehog Proteins; D008055:Lipids; D011506:Proteins; D013438:Sulfhydryl Compounds; D014867:Water; C077245:hh protein, Drosophila