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Structural basis for the acyltransferase activity of lecithin:retinol acyltransferase-like proteins

J Biol Chem. 2012 Jul 6;287(28):23790-807. doi: 10.1074/jbc.M112.361550. Epub 2012 May 17.

Abstract

Lecithin:retinol acyltransferase-like proteins, also referred to as HRAS-like tumor suppressors, comprise a vertebrate subfamily of papain-like or NlpC/P60 thiol proteases that function as phospholipid-metabolizing enzymes. HRAS-like tumor suppressor 3, a representative member of this group, plays a key role in regulating triglyceride accumulation and energy expenditure in adipocytes and therefore constitutes a novel pharmacological target for treatment of metabolic disorders causing obesity. Here, we delineate a catalytic mechanism common to lecithin:retinol acyltransferase-like proteins and provide evidence for their alternative robust lipid-dependent acyltransferase enzymatic activity. We also determined high resolution crystal structures of HRAS-like tumor suppressor 2 and 3 to gain insight into their active site architecture. Based on this structural analysis, two conformational states of the catalytic Cys-113 were identified that differ in reactivity and thus could define the catalytic properties of these two proteins. Finally, these structures provide a model for the topology of these enzymes and allow identification of the protein-lipid bilayer interface. This study contributes to the enzymatic and structural understanding of HRAS-like tumor suppressor enzymes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acylation
  • Acyltransferases / chemistry
  • Acyltransferases / genetics
  • Acyltransferases / metabolism*
  • Amino Acid Sequence
  • Biocatalysis
  • Catalytic Domain
  • Chromatography, High Pressure Liquid
  • Crystallography, X-Ray
  • Cysteine / chemistry
  • Cysteine / genetics
  • Cysteine / metabolism
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Stability
  • Humans
  • Mass Spectrometry
  • Models, Molecular
  • Molecular Sequence Data
  • Phospholipases A2
  • Phospholipases A2, Calcium-Independent / chemistry
  • Phospholipases A2, Calcium-Independent / genetics
  • Phospholipases A2, Calcium-Independent / metabolism*
  • Phospholipids / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Phospholipids
  • Tumor Suppressor Proteins
  • Acyltransferases
  • lecithin-retinol acyltransferase
  • PLAAT2 protein, human
  • PLAAT3 protein, human
  • Phospholipases A2
  • Phospholipases A2, Calcium-Independent
  • Cysteine

Associated data

  • PDB/4DOT
  • PDB/4DPZ