Tear Lipocalin and Lipocalin-Interacting Membrane Receptor

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.

Pulse of inflammatory proteins in the pregnant uterus of European polecats ( Mustela putorius ) leading to the time of implantation

Uterine secretory proteins protect the uterus and conceptuses against infection, facilitate implantation, control cellular damage resulting from implantation, and supply pre-implantation embryos with nutrients. Unlike in humans, the early conceptus of the European polecat ( Mustela putorius ; ferret) grows and develops free in the uterus until implanting at about 12 days after mating. We found that the proteins appearing in polecat uteri changed dramatically with time leading to implantation. Several of these proteins have also been found in pregnant uteri of other eutherian mammals. However, we found a combination of two increasingly abundant proteins that have not been recorded before in pre-placentation uteri. First, the broad-spectrum proteinase inhibitor α 2 -macroglobulin rose to dominate the protein profile by the time of implantation. Its functions may be to limit damage caused by the release of proteinases during implantation or infection, and to control other processes around sites of implantation. Second, lipocalin-1 (also known as tear lipocalin) also increased substantially in concentration. This protein has not previously been recorded as a uterine secretion in pregnancy in any species. If polecat lipocalin-1 has similar biological properties to that of humans, then it may have a combined function in antimicrobial protection and transporting or scavenging lipids. The changes in the uterine secretory protein repertoire of European polecats is therefore unusual, and may be representative of pre-placentation supportive uterine secretions in mustelids (otters, weasels, badgers, mink, wolverines) in general.

Pulse of α-2-macroglobulin and lipocalin-1 in the pregnant uterus of European polecats (Mustela putorius) at the time of implantation

Uterine secretory proteins protect the uterus and conceptuses against infection, facilitate implantation, control cellular damage resulting from implantation, and supply embryos with nutrients. The early conceptus of the European polecat (Mustela putorius) grows and develops free in the uterus until implanting at about 12 days after mating. Using a proteomics approach we found that the proteins appearing in the uterus leading up to and including the time of implantation changed dramatically with time. Several of the proteins identified have been found in pregnant uteri of other placental mammals, such as α1-antitrypsin, serum albumin, lactoferrin, cathepsin L1, uteroferrin, and ectonucleotide pyrophosphatase. The broad-spectrum proteinase inhibitor α2-macroglobulin rose from relatively low abundance initially to dominate the protein profile by the time of implantation. Its functions may be to limit damage caused by the release of proteinases during implantation, and to control other processes around the site of implantation. Lipocalin-1 (also known as tear lipocalin) has not previously been recorded as a uterine secretion in pregnancy, and also increased substantially in concentration. If polecat lipocalin-1 has similar biochemical properties to the human form, then it may have a combined function in transporting or scavenging lipids, and antimicrobial activities. The changes in the uterine secretory proteome of Euroepan polecats may be similar in those species of mustelid that engage in embryonic diapause, but possibly only following reactivation of the embryo.