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Veerkamp, J.H.; Moerkerk, H.T.B. van; Prinsen, Clemens; Kuppevelt, Toin H. Van

doi:10.1023/a:1006866119264

Cited by 71 publications

(19 citation statements)

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“…Our fluorescence binding data showed rat L-FABP binds more than one molecules of ANS (Bmax = 1.4), which is in agreement with previous report of Velkov et al [70]. However our human L-FABP data showed it only bind one ANS molecule (Bmax = 0.8)—in agreement with an earlier fluorescence binding assay report wherein human L-FABP bound one ANS with Kd = 2.0 μM [90]. In contrast, an NMR study showed human L-FABP bound two molecules of ANS [91].…”

Section: Discussionsupporting

confidence: 92%

Structural and functional interaction of fatty acids with human liver fatty acid‐binding protein (L‐FABP) T94A variant

et al. 2014

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The human liver fatty acid binding protein (L-FABP) T94A variant, the most common in the FABP family, has been associated with elevated liver triglyceride (TG) levels. How this amino acid substitution elicits these effects is not known. This issue was addressed with human recombinant wild-type (WT, T94T) and T94A variant L-FABP proteins as well as cultured primary human hepatocytes expressing the respective proteins (genotyped as TT, TC, and CC). T94A substitution did not or only slightly alter L-FABP binding affinities for saturated, monounsaturated, or polyunsaturated long chain fatty acids (LCFA), nor did it change the affinity for intermediates in TG synthesis. Nevertheless, T94A substitution markedly altered the secondary structural response of L-FABP induced by binding LCFA or intermediates of TG synthesis. Finally, T94A substitution markedly diminished polyunsaturated fatty acid, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), induction of peroxisome proliferator-activated receptor alpha (PPARα) - regulated proteins such as L-FABP, fatty acid transport protein 5 (FATP5), and PPARα itself in cultured primary human hepatocytes. Thus, while T94A substitution did not alter the affinity of human L-FABP for LCFAs, it significantly altered human L-FABP structure and stability as well as conformational and functional response to these ligands.

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Section: Discussionsupporting

confidence: 92%

Structural and functional interaction of fatty acids with human liver fatty acid‐binding protein (L‐FABP) T94A variant

et al. 2014

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“…Although their primary structures show strong homology, they exhibit specific fatty acid ligand preferences. FABP3 binds preferentially to ω6 PUFAs such as arachidonic acid (20:4) (20–22), FABP5 prefers saturated fatty acids such as stearic acid (18:0) and monounsaturated fatty acids such as oleic acid (OA, 18:1) (22–24), and FABP7 binds preferentially to ω3 PUFAs such as docosahexaenoic acid (DHA, 22:6) (21,22,25). …”

Section: Introductionmentioning

confidence: 99%

Functional characterization of FABP3, 5 and 7 gene variants identified in schizophrenia and autism spectrum disorder and mouse behavioral studies

Shimamoto

Ohnishi

Maekawa

et al. 2014

Human Molecular Genetics

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Disturbances of lipid metabolism have been implicated in psychiatric illnesses. We previously reported an association between the gene for fatty acid binding protein 7 (FABP7) and schizophrenia. Furthermore, we identified and reported several rare non-synonymous polymorphisms of the brain-expressed genes FABP3, FABP5 and FABP7 from schizophrenia and autism spectrum disorder (ASD), diseases known to part share genetic architecture. Here, we conducted further studies to better understand the contribution these genes make to the pathogenesis of schizophrenia and ASD. In postmortem brains, we detected altered mRNA expression levels of FABP5 in schizophrenia, and of FABP7 in ASD and altered FABP5 in peripheral lymphocytes. Using a patient cohort, comprehensive mutation screening identified six missense and two frameshift variants from the three FABP genes. The two frameshift proteins, FABP3 E132fs and FABP7 N80fs, formed cellular aggregates and were unstable when expressed in cultured cells. The four missense mutants with predicted possible damaging outcomes showed no changes in intracellular localization. Examining ligand binding properties, FABP7 S86G and FABP7 V126L lost their preference for docosahexaenoic acid to linoleic acid. Finally, mice deficient in Fabp3, Fabp5 and Fabp7 were evaluated in a systematic behavioral test battery. The Fabp3 knockout (KO) mice showed decreased social memory and novelty seeking, and Fabp7 KO mice displayed hyperactive and anxiety-related phenotypes, while Fabp5 KO mice showed no apparent phenotypes. In conclusion, disturbances in brain-expressed FABPs could represent an underlying disease mechanism in a proportion of schizophrenia and ASD sufferers.

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“…A blue shift to 512 nm with DAUDA is substantial, but is less than that observed upon DAUDA binding to liver or intestinal fatty acid binding proteins (496 and 492 nm, respectively) (29,30), tear lipocalin (490 nm) (31); the most extreme blue shifts in DAUDA emission have been recorded upon interaction with unusual lipid-binding proteins from nematode worms (475 and 485 nm) (32)(33)(34). The relatively small blue shift when DAUDA interacts with ZAG is perhaps indicative of a binding site that is more solvent-exposed than in lipid transporter proteins, such as would be expected for an open-sided binding groove.…”

Section: Resultsmentioning

confidence: 95%

Hydrophobic Ligand Binding by Zn-α2-glycoprotein, a Soluble Fat-depleting Factor Related to Major Histocompatibility Complex Proteins

Kennedy¹,

Heikema²,

Cooper³

et al. 2001

Journal of Biological Chemistry

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Zn-␣ 2 -glycoprotein (ZAG) is a member of the major histocompatibility complex (MHC) class I family of proteins and is identical in amino acid sequence to a tumorderived lipid-mobilizing factor associated with cachexia in cancer patients. ZAG is present in plasma and other body fluids, and its natural function, like leptin's, probably lies in lipid store homeostasis. X-ray crystallography has revealed an open groove between the helices of ZAG's ␣ 1 and ␣ 2 domains, containing an unidentified small ligand in a position similar to that of peptides in MHC proteins (Sanchez, L. M., Chirino, A. J., and Bjorkman, P. J. (1999) Science 283, 1914 -1919). Here we show, using serum-derived and bacterial recombinant protein, that ZAG binds the fluorophore-tagged fatty acid 11-(dansylamino)undecanoic acid (DAUDA) and, by competition, natural fatty acids such as arachidonic, linolenic, eicosapentaenoic, and docosahexaenoic acids. Other MHC class I-related proteins (FcRn, HFE, HLA-Cw*0702) showed no such evidence of binding. Fluorescence and isothermal calorimetry analysis showed that ZAG binds DAUDA with K d in the micromolar range, and differential scanning calorimetry showed that ligand binding increases the thermal stability of the protein. Addition of fatty acids to ZAG alters its intrinsic (tryptophan) fluorescence emission spectrum, providing a strong indication that ligand binds in the expected position close to a cluster of exposed tryptophan side chains in the groove. This study therefore shows that ZAG binds small hydrophobic ligands, that the natural ligand may be a polyunsaturated fatty acid, and provides a fluorescencebased method for investigating ZAG-ligand interactions. Zn-␣ 2 -glycoprotein (ZAG)1 is a soluble protein present in serum and other body fluids (1, 2). It accumulates in breast cysts, is produced by 40% of breast carcinomas, and is inducible in breast cancer cell lines by glucocorticoids and androgens (2,3). ZAG is identical in amino acid sequence to lipid-mobilizing factor that is associated with cachexia (4, 5), the wasting syndrome involving depletion of adipose and muscle tissue, such as occurs in many patients with cancer, AIDS, trypanosomiasis, and other life-threatening diseases. Significantly, ZAG is overexpressed in tumors that accompany fat loss, and exogenous ZAG produces cachectic symptoms in experimental animals (4, 5). ZAG, like leptin (6), therefore, participates in lipid store homeostasis, the dysregulation of which has serious implications for survival and the management of cancer and other diseases. ZAG is a member of a family of proteins typified by the class I MHC proteins (which present peptides to cytotoxic T cells) (7) and includes CD1 (which presents lipidic antigens to T cells) (8, 9), the neonatal Fc receptor (FcRn; involved in transportation of immunoglobulin across epithelia), and HFE (a transferrinbinding protein that regulates iron homeostasis) (10,11). In contrast to all other MHC-like proteins, ZAG and MIC-A (a divergent member of the MHC family) are not found in asso...

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Cited by 71 publications

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Structural and functional interaction of fatty acids with human liver fatty acid‐binding protein (L‐FABP) T94A variant

Structural and functional interaction of fatty acids with human liver fatty acid‐binding protein (L‐FABP) T94A variant

Functional characterization of FABP3, 5 and 7 gene variants identified in schizophrenia and autism spectrum disorder and mouse behavioral studies

Hydrophobic Ligand Binding by Zn-α2-glycoprotein, a Soluble Fat-depleting Factor Related to Major Histocompatibility Complex Proteins

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