Issue 12, 2019

Sterol A-ring plasticity in hedgehog protein cholesterolysis supports a primitive substrate selectivity mechanism

Abstract

Cholesterolysis of Hedgehog family proteins couples endoproteolysis to protein C-terminal sterylation. The transformation is self-catalyzed by HhC, a partially characterized enzymatic domain found in precursor forms of Hedgehog. Here we explore spatial ambiguity in sterol recognition by HhC, using a trio of derivatives where the sterol A-ring is contracted, fused, or distorted. Sterylation assays indicate that these geometric variants react as substrates with relative activity: cholesterol, 1.000 > A-ring contracted, 0.100 > A-ring fused, 0.020 > A-ring distorted, 0.005. Experimental results and computational sterol docking into the first HhC homology model suggest a partially unstructured binding site with substrate recognition governed in large part by hydrophobic interactions.

Graphical abstract: Sterol A-ring plasticity in hedgehog protein cholesterolysis supports a primitive substrate selectivity mechanism

Supplementary files

Article information

Article type
Communication
Submitted
07 Dec 2018
Accepted
16 Jan 2019
First published
23 Jan 2019

Chem. Commun., 2019,55, 1829-1832

Author version available

Sterol A-ring plasticity in hedgehog protein cholesterolysis supports a primitive substrate selectivity mechanism

D. A. Ciulla, A. G. Wagner, X. Liu, C. L. Cooper, M. T. Jorgensen, C. Wang, P. Goyal, N. K. Banavali, J. L. Pezzullo, J. Giner and B. P. Callahan, Chem. Commun., 2019, 55, 1829 DOI: 10.1039/C8CC09729A

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements