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AIG1 and ADTRP are atypical integral membrane hydrolases that degrade bioactive FAHFAs

Academic Article
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Overview

related to degree

  • Cognetta III, Armand B, Ph.D. in Chemical Biology, Scripps Research 2013 - 2018
  • Hulce, Jonathan J, Ph.D. in Chemistry, Scripps Research 2010 - 2015

authors

  • Parsons, W. H.
  • Kolar, M. J.
  • Kamat, S. S.
  • Cognetta III, Armand B
  • Hulce, Jonathan J
  • Saez, Enrique
  • Kahn, B. B.
  • Saghatelian, Alan
  • Cravatt, Benjamin

publication date

  • May 2016

journal

  • Nature Chemical Biology  Journal

abstract

  • Enzyme classes may contain outlier members that share mechanistic, but not sequence or structural, relatedness with more common representatives. The functional annotation of such exceptional proteins can be challenging. Here, we use activity-based profiling to discover that the poorly characterized multipass transmembrane proteins AIG1 and ADTRP are atypical hydrolytic enzymes that depend on conserved threonine and histidine residues for catalysis. Both AIG1 and ADTRP hydrolyze bioactive fatty acid esters of hydroxy fatty acids (FAHFAs) but not other major classes of lipids. We identify multiple cell-active, covalent inhibitors of AIG1 and show that these agents block FAHFA hydrolysis in mammalian cells. These results indicate that AIG1 and ADTRP are founding members of an evolutionarily conserved class of transmembrane threonine hydrolases involved in bioactive lipid metabolism. More generally, our findings demonstrate how chemical proteomics can excavate potential cases of convergent or parallel protein evolution that defy conventional sequence- and structure-based predictions.

subject areas

  • Amino Acid Sequence
  • Cloning, Molecular
  • Esters
  • Fatty Acids
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Hydrolases
  • Hydroxy Acids
  • Membrane Proteins
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
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Identity

PubMed Central ID

  • PMC4837090

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio.2051

PubMed ID

  • 27018888
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Additional Document Info

start page

  • 367

end page

  • 372

volume

  • 12

issue

  • 5

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