Fatty Acyl Recognition and Transfer by an Integral Membrane S-acyltransferase

Science. 2018 Jan 12;359(6372):eaao6326. doi: 10.1126/science.aao6326.

Abstract

DHHC (Asp-His-His-Cys) palmitoyltransferases are eukaryotic integral membrane enzymes that catalyze protein palmitoylation, which is important in a range of physiological processes, including small guanosine triphosphatase (GTPase) signaling, cell adhesion, and neuronal receptor scaffolding. We present crystal structures of two DHHC palmitoyltransferases and a covalent intermediate mimic. The active site resides at the membrane-cytosol interface, which allows the enzyme to catalyze thioester-exchange chemistry by using fatty acyl-coenzyme A and explains why membrane-proximal cysteines are candidates for palmitoylation. The acyl chain binds in a cavity formed by the transmembrane domain. We propose a mechanism for acyl chain-length selectivity in DHHC enzymes on the basis of cavity mutants with preferences for shorter and longer acyl chains.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acyl Coenzyme A / metabolism*
  • Acyltransferases / chemistry*
  • Acyltransferases / genetics
  • Acyltransferases / metabolism
  • Animals
  • Catalytic Domain
  • Crystallization
  • Crystallography, X-Ray
  • Cysteine / chemistry
  • Humans
  • Lipoylation
  • Models, Molecular
  • Mutation
  • Protein Domains
  • Protein Structure, Secondary
  • Substrate Specificity
  • Zebrafish Proteins / chemistry*
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism

Substances

  • Acyl Coenzyme A
  • Zebrafish Proteins
  • Acyltransferases
  • ZDHHC20 protein, human
  • Cysteine