6do7

<StructureSection load='6do7' size='340' side='right'caption='[[6do7]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''>

<table><tr><td colspan='2'>[[6do7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DO7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DO7 FirstGlance]. <br>

</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FABP1, FABPL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6do7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6do7 OCA], [http://pdbe.org/6do7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6do7 RCSB], [http://www.ebi.ac.uk/pdbsum/6do7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6do7 ProSAT]</span></td></tr>

[[http://www.uniprot.org/uniprot/FABPL_HUMAN FABPL_HUMAN]] Binds free fatty acids and their coenzyme A derivatives, bilirubin, and some other small molecules in the cytoplasm. May be involved in intracellular lipid transport.

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a transcriptional regulator of lipid metabolism. GW7647 is a potent PPARalpha agonist that must reach the nucleus to activate this receptor. In cells expressing human fatty acid-binding protein 1 (FABP1), GW7647 treatment increases FABP1's nuclear localization, and potentiates GW7647-mediated PPARalpha activation; GW7647 is less effective in cells that do not express FABP1. To elucidate the underlying mechanism, here we substituted residues in FABP1 known to dictate lipid signaling by other intracellular lipid-binding proteins. Substitutions of Lys-20 and Lys-31 to Ala in the FABP1 helical cap affected neither its nuclear localization nor PPARalpha activation. In contrast, Ala substitution of Lys-57, Glu-77, and Lys-96, located in the loops adjacent to the ligand-binding portal region, abolished both FABP1 nuclear localization and GW7647-induced PPARalpha activation, but had little effect on GW7647-FABP1 binding affinity. Using solution NMR spectroscopy, we determined the wildtype FABP1 structure and analyzed the dynamics in the apo and GW7647-bound structures of both the wildtype and the K57A/E77A/K96A triple mutant. We found that GW7647 binding causes little change in the FABP1 backbone, but solvent-exposes several residues in the loops around the portal region, including Lys-57, Glu-77, and Lys-96. These residues also become more solvent exposed upon binding of FABP1 with the endogenous PPARalpha agonist oleic acid. Together with previous observations, our findings suggest that GW7647 binding stabilizes a FABP1 conformation that promotes its interaction with PPARalpha. We conclude that full PPARalpha agonist activity of GW7647 requires FABP1-dependent transport and nuclear localization processes.

A ligand-induced structural change in fatty acid-binding protein 1 is associated with potentiation of peroxisome proliferator-activated receptor alpha agonists.,Patil R, Mohanty B, Liu B, Chandrashekaran IR, Headey SJ, Williams ML, Clements CS, Ilyichova O, Doak BC, Genissel P, Weaver RJ, Vuillard L, Halls ML, Porter CJH, Scanlon MJ J Biol Chem. 2018 Dec 31. pii: RA118.006848. doi: 10.1074/jbc.RA118.006848. PMID:30598509<ref>PMID:30598509</ref>

 

[[Category: Human]]

[[Category: Doak, B C]]

[[Category: Mohanty, B]]

[[Category: Patil, R]]

[[Category: Scanlon, M J]]

[[Category: Lipid binding protein]]