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

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.

Results from:
Golczak M, Kiser PD, Sears AE, Lodowski DT, Blaner WS, Palczewski K.
J Biol Chem. 2012 Jul 6;287(28):23790-807. doi: 10.1074/jbc.M112.361550. Epub 2012 May 17.
PMID: 22605381[PubMed - indexed for MEDLINE]
PMCID: PMC3390653 [Available on 2013/7/6]