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

Publication Type:

Journal Article


J Biol Chem, Volume 287, Issue 28, p.23790-807 (2012)


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


<p>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.</p>