Reactome | Autoproteolytic cleavage of Hh precursors

Autoproteolytic cleavage of Hh precursors

Stable Identifier

R-HSA-5358340

Type

Reaction [transition]

Species

Homo sapiens

Compartment

endoplasmic reticulum lumen

ReviewStatus

5/5

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Autoproteolytic cleavage of Hh precursors

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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 Porter, JA, Young, KE, Beachy, PA	Science	1996
7885476	The product of hedgehog autoproteolytic cleavage active in local and long-range signalling Porter, JA, von Kessler, DP, Ekker, SC, Young, KE, Lee, JJ, Moses, K, Beachy, PA	Nature	1995
15292211	Functional characterization of sonic hedgehog mutations associated with holoprosencephaly Traiffort, E, Dubourg, C, Faure, H, Rognan, D, Odent, S, Durou, MR, David, V, 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 Roessler, E, El-Jaick, KB, Dubourg, C, Vélez, JI, Solomon, BD, Pineda-Alvarez, DE, Lacbawan, F, Zhou, N, Ouspenskaia, M, Paulussen, A, Smeets, HJ, Hehr, U, Bendavid, C, Bale, S, Odent, S, David, V, Muenke, M	Hum. Mutat.	2009
16611729	Cholesterol modification restricts the spread of Shh gradient in the limb bud Li, Y, Zhang, H, Litingtung, Y, Chiang, C	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, Wolf, A, Wagner, M, Kuhlmann, J, Waldmann, H	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, Litingtung, Y, Chiang, C	Development	2007
7985023	Autoproteolysis in hedgehog protein biogenesis Lee, JJ, Ekker, SC, von Kessler, DP, Porter, JA, Sun, BI, Beachy, PA	Science	1994
21357747	Processing and turnover of the Hedgehog protein in the endoplasmic reticulum Chen, X, Tukachinsky, H, Huang, CH, Jao, C, Chu, YR, Tang, HY, Mueller, B, Schulman, S, Rapoport, TA, Salic, A	J. Cell Biol.	2011
16282375	Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly Maity, T, Fuse, N, Beachy, PA	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, Zeng, C, Wen, D, Rayhorn, P, Baker, DP, Williams, KP, Bixler, SA, Ambrose, CM, Garber, EA, Miatkowski, K, Taylor, FR, Wang, EA, Galdes, A	J. Biol. Chem.	1998
8689684	Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain Porter, JA, Ekker, SC, Park, WJ, von Kessler, DP, Young, KE, Chen, CH, Ma, Y, Woods, AS, Cotter, RJ, Koonin, EV, Beachy, PA	Cell	1996
19081070	Hedgehog signaling in development and cancer Jiang, J, Hui, CC	Dev. Cell	2008