P4HB forms mixed disulphides with Hh precursors

Stable Identifier
Reaction [binding]
Homo sapiens
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Hh ligands undergo a autoproteolytic cleavage mediated by a conserved residue in the C-terminal region to yield an N-terminal fragment destined for further modification and secretion, and a C-terminal fragment that is subsequently degraded by ERAD (reviewed in Gallet, 2011). Recent work has shown that autoproteolytic cleavage of Hh ligands depends on prior formation of an intramolecular disulphide bond between the catalytic cysteine residue and another conserved cysteine residue in the C-terminal region of the precursor (Chen et al, 2011). Mutation of either of these cysteine residues abolishes cleavage, suggesting that the intramolecular disulphide bond is required to establish a catalytically active conformation of the precursor (Chen et al, 2011).

Prior to the autoproteolytic cleavage reaction, the protein disulphide isomerase P4HB is required to reduce the intramolecular disulphide, freeing the catalytic cysteine side chain for nucleophilic attack. Mutational analysis and co-immunoprecipitation studies support a model where the N-terminal CXXC motif of P4HB forms a mixed disulphide with the non-catalytic cysteine residue of the Hh precursor (Chen et al, 2011.
Literature References
PubMed ID Title Journal Year
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
21257310 Hedgehog morphogen: from secretion to reception

Gallet, A

Trends Cell Biol. 2011
Orthologous Events
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