Structural highlights
Function
[HRSL3_HUMAN] Exhibits PLA1/2 activity, catalyzing the calcium-independent hydrolysis of acyl groups in various phosphatidylcholines (PC) and phosphatidylethanolamine (PE). For most substrates, PLA1 activity is much higher than PLA2 activity. Specifically catalyzes the release of fatty acids from phospholipids in adipose tissue (By similarity). N- and O-acylation activity is hardly detectable. Might decrease protein phosphatase 2A (PP2A) activity.[1] [2]
Publication Abstract from PubMed
Cellular uptake of vitamin A, production of visual chromophore and triglyceride homeostasis in adipocytes depend on two representatives of the vertebrate N1pC/P60 protein family, lecithin:retinol acyltransferase (LRAT) and HRAS-like tumor suppressor 3 (HRASLS3). Both proteins function as lipid-metabolizing enzymes but differ in their substrate preferences and dominant catalytic activity. The mechanism of this catalytic diversity is not understood. Here, by using a gain-of-function approach, we identified a specific sequence responsible for the substrate specificity of N1pC/P60 proteins. A 2.2-A crystal structure of the HRASLS3-LRAT chimeric enzyme in a thioester catalytic intermediate state revealed a major structural rearrangement accompanied by three-dimensional domain swapping dimerization not observed in native HRASLS proteins. Structural changes affecting the active site environment contributed to slower hydrolysis of the catalytic intermediate, supporting efficient acyl transfer. These findings reveal structural adaptation that facilitates selective catalysis and mechanism responsible for diverse substrate specificity within the LRAT-like enzyme family.
LRAT-specific domain facilitates vitamin A metabolism by domain swapping in HRASLS3.,Golczak M, Sears AE, Kiser PD, Palczewski K Nat Chem Biol. 2015 Jan;11(1):26-32. doi: 10.1038/nchembio.1687. Epub 2014 Nov, 10. PMID:25383759[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nazarenko I, Schafer R, Sers C. Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells. J Cell Sci. 2007 Apr 15;120(Pt 8):1393-404. Epub 2007 Mar 20. PMID:17374643 doi:http://dx.doi.org/10.1242/jcs.000018
- ↑ Uyama T, Jin XH, Tsuboi K, Tonai T, Ueda N. Characterization of the human tumor suppressors TIG3 and HRASLS2 as phospholipid-metabolizing enzymes. Biochim Biophys Acta. 2009 Dec;1791(12):1114-24. doi:, 10.1016/j.bbalip.2009.07.001. Epub 2009 Jul 14. PMID:19615464 doi:http://dx.doi.org/10.1016/j.bbalip.2009.07.001
- ↑ Golczak M, Sears AE, Kiser PD, Palczewski K. LRAT-specific domain facilitates vitamin A metabolism by domain swapping in HRASLS3. Nat Chem Biol. 2015 Jan;11(1):26-32. doi: 10.1038/nchembio.1687. Epub 2014 Nov, 10. PMID:25383759 doi:http://dx.doi.org/10.1038/nchembio.1687
