Structural model of human PORCN illuminates disease-associated variants and drug-binding sites.
Wnt signaling is essential for normal development and is a therapeutic target in cancer. The enzyme PORCN, or porcupine, is a membrane-bound O-acyltransferase (MBOAT) that is required for the post-translational modification of all Wnts, adding an essential mono-unsaturated palmitoleic acid to a serine on the tip of Wnt hairpin 2. Inherited mutations in PORCN cause focal dermal hypoplasia, and therapeutic inhibition of PORCN slows the growth of Wnt-dependent cancers. Based on homology to mammalian MBOAT proteins, we developed and validated a structural model of human PORCN. The model accommodates palmitoleoyl-CoA and Wnt hairpin 2 in two tunnels in the conserved catalytic core, shedding light on the catalytic mechanism. The model predicts how previously uncharacterized human variants of uncertain significance can alter PORCN function. Drugs including ETC-159, IWP-L6 and LGK-974 dock in the PORCN catalytic site, providing insights into PORCN pharmacologic inhibition. This structural model enhances our mechanistic understanding of PORCN substrate recognition and catalysis, as well as the inhibition of its enzymatic activity, and can facilitate the development of improved inhibitors and the understanding of disease-relevant PORCN mutants. This article has an associated First Person interview with the joint first authors of the paper.
Duke Scholars
Altmetric Attention Stats
Dimensions Citation Stats
Published In
DOI
EISSN
Publication Date
Volume
Issue
Location
Related Subject Headings
- Pharmaceutical Preparations
- Models, Structural
- Membrane Proteins
- Humans
- Focal Dermal Hypoplasia
- Developmental Biology
- Catalytic Domain
- Animals
- Acyltransferases
- 3101 Biochemistry and cell biology
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Location
Related Subject Headings
- Pharmaceutical Preparations
- Models, Structural
- Membrane Proteins
- Humans
- Focal Dermal Hypoplasia
- Developmental Biology
- Catalytic Domain
- Animals
- Acyltransferases
- 3101 Biochemistry and cell biology