The ghrelin O-acyltransferase structure reveals a catalytic channel for transmembrane hormone acylation

Maria B. Campaña, Flaviyan Jerome Irudayanathan, Tasha R. Davis, Kayleigh R. McGovern-Gooch, Rosemary Loftus, Mohammad Ashkar, Najae Escoffery, Melissa Navarro, Michelle A. Sieburg, Shikha Nangia, James L. Hougland

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Integral membrane proteins represent a large and diverse portion of the proteome and are often recalcitrant to purification, impeding studies essential for understanding protein structure and function. By combining co-evolutionary constraints and computational modeling with biochemical validation through site-directed mutagenesis and enzyme activity assays, we demonstrate here a synergistic approach to structurally model purification-resistant topologically complex integral membrane proteins. We report the first structural model of a eukaryotic membrane-bound O-acyltransferase (MBOAT), ghrelin O-acyltransferase (GOAT), which modifies the metabolism-regulating hormone ghrelin. Our structure, generated in the absence of any experimental structural data, revealed an unanticipated strategy for transmembrane protein acylation with catalysis occurring in an internal channel connecting the endoplasmic reticulum lumen and cytoplasm. This finding validated the power of our approach to generate predictive structural models for other experimentally challenging integral membrane proteins. Our results illuminate novel aspects of membrane protein function and represent key steps for advancing structure-guided inhibitor design to target therapeutically important but experimentally intractable membrane proteins.

Original languageEnglish (US)
Pages (from-to)14166-14174
Number of pages9
JournalJournal of Biological Chemistry
Volume294
Issue number39
DOIs
StatePublished - Jan 1 2019

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Campaña, M. B., Irudayanathan, F. J., Davis, T. R., McGovern-Gooch, K. R., Loftus, R., Ashkar, M., Escoffery, N., Navarro, M., Sieburg, M. A., Nangia, S., & Hougland, J. L. (2019). The ghrelin O-acyltransferase structure reveals a catalytic channel for transmembrane hormone acylation. Journal of Biological Chemistry, 294(39), 14166-14174. https://doi.org/10.1074/jbc.AC119.009749