Open AccessHedgehog proteins create a dynamic cholesterol interface
Author(s) -
Amirhossein Mafi,
R.K. Purohit,
Erika Vielmas,
Alexa R. Lauinger,
Brandon Lam,
Yu-Shiuan Cheng,
Tianyi Zhang,
Yiran Huang,
SooKyung Kim,
William A. Goddard,
Alison E. Ondrus
Publication year - 2021
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0246814
Subject(s) - morphogen , hedgehog , intein , hedgehog signaling pathway , biology , chemistry , microbiology and biotechnology , biochemistry , signal transduction , gene , rna , rna splicing
During formation of the Hedgehog (Hh) signaling proteins, cooperative activities of the Hedgehog INTein (Hint) fold and Sterol Recognition Region (SRR) couple autoproteolysis to cholesterol ligation. The cholesteroylated Hh morphogens play essential roles in embryogenesis, tissue regeneration, and tumorigenesis. Despite the centrality of cholesterol in Hh function, the full structure of the Hint-SRR (“Hog”) domain that attaches cholesterol to the last residue of the active Hh morphogen remains enigmatic. In this work, we combine molecular dynamics simulations, photoaffinity crosslinking, and mutagenesis assays to model cholesterolysis intermediates in the human Sonic Hedgehog (hSHH) protein. Our results provide evidence for a hydrophobic Hint-SRR interface that forms a dynamic, non-covalent cholesterol-Hog complex. Using these models, we suggest a unified mechanism by which Hh proteins can recruit, sequester, and orient cholesterol, and offer a molecular basis for the effects of disease-causing hSHH mutations.