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SL Beck, GW Laurie; Putative Functional Domains of the Highly Conserved Pro-Secretory Mitogen Lacritin . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3149.
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Purpose:Lacritin, a novel pro-secretory mitogen expressed predominantly in human lacrimal gland, acts on acinar, ductal and corneal epithelial cells (Sanghi et al, J. Mol. Biol 310:127-39, '01) at low nanomolar estimated Kd through an undetermined mechanism. Here, we searched for structural features indicative of functional domain(s); and as a gauge of its potential importance, compared lacritin's evolutionary conservation with that of other mitogens and tear proteins. Methods:Lacritin's secondary structure was analyzed with HelicalWheel and Peptide Structure in Seqweb (GCG). Comparative conservation was studied with NCBI's Unigene. Results:Lacritin's C-terminus contains two putative amphipathic α-helices of 24 (amphi-1) and 19 (amphi-2) residues in length. Amphi-2 appears to be of class H, which mediate hormone-receptor ligation. Amphi-1 does not fall neatly into any category, but has hydrophobic and hydrophilic faces of approximately 180 degrees, each interrupted by two or three residues. Lacritin's high target cell specificity (Walton et al, unpublished) is in keeping with an Amphi-2 receptor-mediated mechanism. Based on the known two-thirds of rat lacritin nucleotide sequence, rat and human lacritin share 99% amino acid identity, a level uncommon in most tear proteins, which are conserved between 40-65%. For example, the percent identity of human and rat lipocalin-1, salivary proline-rich protein, and cystatin A are 60%, 51%, and 58% respectively. In contrast, there is much higher human-rat identity of the growth factors HGF (99%), FGF-1 (95%), and TGF-b1 (89%). Conclusion:Lacritin, secreted from lacrimal acini, boosts secretion in an autocrine manner, possibly by ligation of amphi-2 to an apical cell surface receptor. In the lacrimal ducts it enhances cell proliferation, and perhaps development and turnover, through a signaling pathway involving tyrosine phosphorylation. It then flows over the cornea, causing rapid calcium signaling, and potentially enhancing wound healing.
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