Dataset Information

Ligand binding site of tear lipocalin: contribution of a trigonal cluster of charged residues probed by 8-anilino-1-naphthalenesulfonic acid.

ABSTRACT: Human tear lipocalin (TL) exhibits diverse functions, most of which are linked to ligand binding. To map the binding site of TL for some amphiphilic ligands, we capitalized on the hydrophobic and hydrophilic properties of 8-anilino-1-naphthalenesulfonic acid (ANS). In single Trp mutants, resonance energy transfer from Trp to ANS indicates that the naphthalene group of ANS is proximate to Leu105 in the cavity. Binding energies of TL to ANS and its analogues reveal contributions from electrostatic interactions. The sulfonate group of ANS interacts strongly with the nonconserved intracavitary residue Lys114 and less with neighboring residues His84 and Glu34. This trigonal cluster of residues may play a role in the ligand recognition site for some negatively charged ligands. Because many drugs possess sulfonate groups, the trigonal cluster-sulfonate interaction can also be exploited as a lipocalin-based drug delivery mechanism. The binding of lauric acid and its analogues shows that fatty acids assume heterogeneous orientations in the cavity of TL. Predominantly, the hydrocarbon tail is buried in the cavity of TL and the carboxyl group is oriented toward the mouth. However, TL can also interact, albeit relatively weakly, with fatty acids oriented in the opposite direction. As the major lipid binding protein of tears, the ability to accommodate fatty acids in two opposing orientations may have functional implications for TL. At the aqueous-lipid interface, fatty acids whose carboxyl groups are positioned toward the aqueous phase are available for interaction with TL that could augment stability of the tear film.

SUBMITTER: Gasymov OK

PROVIDER: S-EPMC2873144 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Ligand binding site of tear lipocalin: contribution of a trigonal cluster of charged residues probed by 8-anilino-1-naphthalenesulfonic acid.

Gasymov Oktay K OK Abduragimov Adil R AR Glasgow Ben J BJ

Biochemistry 20080108 5

Human tear lipocalin (TL) exhibits diverse functions, most of which are linked to ligand binding. To map the binding site of TL for some amphiphilic ligands, we capitalized on the hydrophobic and hydrophilic properties of 8-anilino-1-naphthalenesulfonic acid (ANS). In single Trp mutants, resonance energy transfer from Trp to ANS indicates that the naphthalene group of ANS is proximate to Leu105 in the cavity. Binding energies of TL to ANS and its analogues reveal contributions from electrostatic ...[more]

PMID: 18179255

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Project description:Tear lipocalin is a primate protein that was recognized as a lipocalin from the homology of the primary sequence. The protein is most concentrated in tears and produced by lacrimal glands. Tear lipocalin is also produced in the tongue, pituitary, prostate, and the tracheobronchial tree. Tear lipocalin has been assigned a multitude of functions. The functions of tear lipocalin are inexorably linked to structural characteristics that are often shared by the lipocalin family. These characteristics result in the binding and or transport of a wide range of small hydrophobic molecules. The cavity of tear lipocalin is formed by eight strands (A-H) that are arranged in a β-barrel and are joined by loops between the β-strands. Recently, studies of the solution structure of tear lipocalin have unveiled new structural features such as cation-π interactions, which are extant throughout the lipocalin family. Lipocalin has many unique features that affect ligand specificity. These include a capacious and a flexible cavity with mobile and short overhanging loops. Specific features that confer promiscuity for ligand binding in tear lipocalin will be analyzed. The functions of tear lipocalin include the following: antimicrobial activities, scavenger of toxic and tear disruptive compounds, endonuclease activity, and inhibition of cysteine proteases. In addition, tear lipocalin binds and may modulate lipids in the tears. Such actions support roles as an acceptor for phospholipid transfer protein, heteropolymer formation to alter viscosity, and tear surface interactions. The promiscuous lipid-binding properties of tear lipocalin have created opportunities for its use as a drug carrier. Mutant analogs have been created to bind other molecules such as vascular endothelial growth factor for medicinal use. Tear lipocalin has been touted as a useful biomarker for several diseases including breast cancer, chronic obstructive pulmonary disease, diabetic retinopathy, and keratoconus. The functional possibilities of tear lipocalin dramatically expanded when a putative receptor, lipocalin-interacting membrane receptor was identified. However, opposing studies claim that lipocalin-interacting membrane receptor is not specific for lipocalin. A recent study even suggests a different function for the membrane protein. This controversy will be reviewed in light of gene expression data, which suggest that tear lipocalin has a different tissue distribution than the putative receptor. But the data show lipocalin-interacting membrane receptor is expressed on ocular surface epithelium and that a receptor function here would be rational.

Dataset Information

Ligand binding site of tear lipocalin: contribution of a trigonal cluster of charged residues probed by 8-anilino-1-naphthalenesulfonic acid.

Publications

Ligand binding site of tear lipocalin: contribution of a trigonal cluster of charged residues probed by 8-anilino-1-naphthalenesulfonic acid.

Similar Datasets

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