Autoproteolytic cleavage of Hh precursors

Stable Identifier
Reaction [transition]
Homo sapiens
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Autoproteolytic processing of the Hh precursor is essential for the production of active secreted Hh ligand and mutants that disrupt this processing have been identified in the congenital nervous system disorder holoprosencephaly (Traiffort et al, 2004; Maity et al, 2005; Roessler et al, 2009; reviewed in Jiang et al, 2008). Cleavage of Hh occurs through two nucleophilic substitutions. The first step is mediated by the catalytic cysteine residue, which is found in a conserved G-C-F motif. The cysteine side chain attacks the carbonyl carbon of the main peptide chain between the glycine and cysteine residues, replacing the amino group in the peptide backbone with a thioester linkage (Lee et al, 1994; Porter et al, 1995; Porter et al, 1996a, b; Chen et al, 2011). The second step involves nucleophilic attack of the same carbonyl group by cholesterol. This step displaces the C-terminal fragment (Hh-C) of the Hh precursor and results in the formation of the N-terminal fragment (Hh-Np) modified at its C-terminus by an ester linkage with cholesterol (Porter et al, 1996a, b; Chen et al, 2011). Cholesterol modification appears to contribute to further processing and trafficking of the Hh ligand, as engineered forms of vertebrate and fly Hh that lack cholesterol are not efficiently palmitoylated (Pepinsky et al, 1998). Cholesterol also restricts the diffusion of the secreted ligand by interacting with the lipid bilayer of the secreting cell. Consistent with this, aberrant activation of Hh target genes is seen in the absence of cholesterol modification (Peters et al, 2004; Guerrero et al, 2007; Li et al, 2006; Huang et al, 2007).

Literature References
PubMed ID Title Journal Year
8824192 Cholesterol modification of hedgehog signaling proteins in animal development

Beachy, PA, Porter, JA, Young, KE

Science 1996
7885476 The product of hedgehog autoproteolytic cleavage active in local and long-range signalling

von Kessler, DP, Moses, K, Beachy, PA, Lee, JJ, Young, KE, Ekker, SC, Porter, JA

Nature 1995
15292211 Functional characterization of sonic hedgehog mutations associated with holoprosencephaly

David, V, Traiffort, E, Odent, S, Faure, H, Durou, MR, Rognan, D, Dubourg, C, Ruat, M

J. Biol. Chem. 2004
19603532 The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis

Pineda-Alvarez, DE, Hehr, U, Bale, S, Zhou, N, Odent, S, Roessler, E, David, V, Bendavid, C, VĂ©lez, JI, Dubourg, C, Ouspenskaia, M, El-Jaick, KB, Lacbawan, F, Paulussen, A, Smeets, HJ, Solomon, BD, Muenke, M

Hum. Mutat. 2009
16611729 Cholesterol modification restricts the spread of Shh gradient in the limb bud

Li, Y, Chiang, C, Zhang, H, Litingtung, Y

Proc. Natl. Acad. Sci. U.S.A. 2006
15163793 The cholesterol membrane anchor of the Hedgehog protein confers stable membrane association to lipid-modified proteins

Peters, C, Kuhlmann, J, Wolf, A, Waldmann, H, Wagner, M

Proc. Natl. Acad. Sci. U.S.A. 2004
17507410 Region-specific requirement for cholesterol modification of sonic hedgehog in patterning the telencephalon and spinal cord

Huang, X, Chiang, C, Litingtung, Y

Development 2007
7985023 Autoproteolysis in hedgehog protein biogenesis

von Kessler, DP, Beachy, PA, Lee, JJ, Sun, BI, Porter, JA, Ekker, SC

Science 1994
21357747 Processing and turnover of the Hedgehog protein in the endoplasmic reticulum

Jao, C, Rapoport, TA, Tang, HY, Chu, YR, Schulman, S, Huang, CH, Chen, X, Salic, A, Mueller, B, Tukachinsky, H

J. Cell Biol. 2011
16282375 Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly

Beachy, PA, Fuse, N, Maity, T

Proc. Natl. Acad. Sci. U.S.A. 2005
17126548 A conserved mechanism of Hedgehog gradient formation by lipid modifications

Guerrero, I, Chiang, C

Trends Cell Biol. 2007
9593755 Identification of a palmitic acid-modified form of human Sonic hedgehog

Pepinsky, RB, Galdes, A, Williams, KP, Garber, EA, Wen, D, Wang, EA, Bixler, SA, Miatkowski, K, Rayhorn, P, Taylor, FR, Ambrose, CM, Zeng, C, Baker, DP

J. Biol. Chem. 1998
8689684 Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain

Woods, AS, Koonin, EV, Cotter, RJ, von Kessler, DP, Chen, CH, Beachy, PA, Park, WJ, Ma, Y, Young, KE, Ekker, SC, Porter, JA

Cell 1996
19081070 Hedgehog signaling in development and cancer

Hui, CC, Jiang, J

Dev. Cell 2008
Catalyst Activity

endopeptidase activity of NglycoAsn-Hh precursors:P4HB [endoplasmic reticulum lumen]

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