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Defining roles of the sterol recognition region in Hedgehog cholesterolyation

Purohit, Rahul and Vielmas, Erika and Peng, Daniel S. and Ondrus, Alison (2020) Defining roles of the sterol recognition region in Hedgehog cholesterolyation. FASEB Journal, 34 (S1). p. 1. ISSN 0892-6638. https://resolver.caltech.edu/CaltechAUTHORS:20201009-132957722

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Abstract

The Hedgehog (Hh) signaling pathway plays an essential role during embryogenesis and when dysregulated, can lead to human cancer (basal cell carcinomas) and the most lethal form of juvenile medulloblastoma. Binding of the Hh ligand to its receptor Patched (Ptch) relieves inhibition of the GPCR protein Smoothened (Smo) leading to activation of the Gli transcription factors and changes in target gene expression. The Hh ligand is decorated with two covalent modifications, N‐terminal palmitoylation and C‐terminal cholesterolyation. Hh proteins are synthesized as approximately 45 kDa full‐length species, whereupon a unique process yields the mature morphogen: an autocatalytic cleavage that splits the protein in two and attaches cholesterol to the newly formed C‐terminus. Of the two approximately equal molecular weight cleavage products, the dually lipidated N‐terminal fragment (Hh‐N/“Hog” domain) constitutes the classical Hh morphogen, whereas the C‐terminus (Hh‐C/“Hint”) is responsible for the cleavage reaction. In order to elucidate the chemical mechanism of cholesterolyation, we have determined the roles of the previously uncharacterized sterol recognition region (SRR) in Hh proteins. Using bioinformatics, alanine scanning, and biochemical assays we have identified key motifs and specified residues of the SRR that are required for biochemical processing of Hh. These results provide a first in detail insights into the role of this unique small region of the Hh protein that is capable of cellular targeting and engaging cholesterol to generate an active Hh ligand.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1096/fasebj.2020.34.s1.09381DOIArticle
ORCID:
AuthorORCID
Purohit, Rahul0000-0001-9712-4277
Vielmas, Erika0000-0003-0263-7278
Peng, Daniel S.0000-0002-5218-4599
Ondrus, Alison0000-0002-6023-3290
Additional Information:© 2020 FASEB. Issue Online: 19 April 2020. This work was supported by the Margaret E. Early Medical Research Trust.
Funders:
Funding AgencyGrant Number
Margaret E. Early Medical Research TrustUNSPECIFIED
Issue or Number:S1
Record Number:CaltechAUTHORS:20201009-132957722
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20201009-132957722
Official Citation:Purohit, R., Vielmas, E., Peng, D.S. and Ondrus, A. (2020), Defining roles of the sterol recognition region in Hedgehog cholesterolyation. The FASEB Journal, 34: 1-1. doi:10.1096/fasebj.2020.34.s1.09381
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105970
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 Oct 2020 20:38
Last Modified:09 Oct 2020 20:38

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