Structural and evolutionary studies of a lipocalin: the alpha1-microglobulin protein and its gene

University dissertation from Annika Lindqvist, Molecular Signalling, Cell & Molecular Biolgy, P.O.Box 94, 221 00 Lund, SWEDEN

Abstract: a1-microglobulin is a small glycoprotein present in plasma and in tissues surrounding the gastrointestinal and respiratory tracts. a1-microglobulin is a member of the lipocalin protein family and exhibits several of the typical traits of a lipocalin; it binds an unknown ligand which causes the brown color of the protein, it forms complexes with various different proteins and there have been indications of the presence of a receptor for a1-microglobulin on T-lymphocytes. The function of a1-microglobulin is still unknown. This thesis describes the identification of features in the a1-microglobulin protein and its gene that have been conserved during evolution and might be of importance for the function of the protein. For that purpose the a1-microglobulin protein from cow and plaice, the a1-microglobulin cDNA from rat and cow and the mouse a1-microglobulin gene have been isolated and characterized. The information collected have then been used in comparison with data from characterizations of a1-microglobulin from other species. It showed that the small size, the globular shape and the heterogeneous charge are preserved in all species, as well as the presence of a brown chromophore. This chromophore was also shown to be present in a1-microglobulin isolated from plaice liver, indicating that the attachment of the chromophore is an intracellular event. The glycosylation patterns of the protein are very diverse, ranging from the nonglycosylated frog to three carbohydrate substitutions in human. However, one site for N-linked carbohydrate glycosylation is present in all mammals. Thirty-eight of the amino acid residues in a1-microglobulin are completely conserved, seven of which are specific for the lipocalin family. a1-microglobulin is coexpressed with bikunin, a protease inhibitor, in rat and cow, as well as in other species. The a1-microglobulin/bikunin gene consists of two exon clusters, one that codes for a1-microglobulin and one that contains the exons encoding bikunin. These clusters are flanked and separated by potential recombinatory hot-spots, as seen by the presence of retroelements.

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