The 1.8-A crystal structure of human tear lipocalin reveals an extended branched cavity with capacity for multiple ligands.
In contrast with earlier assumptions, which classified human tear lipocalin (Tlc) as an outlier member of the lipocalin protein family, the 1.8-A resolution crystal structure of the recombinant apoprotein confirms the typical eight-stranded antiparallel beta-barrel architecture with an alpha-helix attached to it. The fold of Tlc most closely resembles the bovine dander allergen Bos d 2, a well characterized prototypic lipocalin, but also reveals similarity with beta-lactoglobulin. However, compared with other lipocalin structures Tlc exhibits an extremely wide ligand pocket, whose entrance is formed by four partially disordered loops. The cavity deeply extends into the beta-barrel structure, where it ends in two distinct lobes. This unusual structural feature explains the known promiscuity of Tlc for various ligands, with chemical structures ranging from lipids and retinoids to the macrocyclic antibiotic rifampin and even to microbial siderophores. Notably, earlier findings of biological activity as a thiol protease inhibitor have no correspondence in the three-dimensional structure of Tlc, rather it appears that its proteolytic fragments could be responsible for this phenomenon. Hence, the present structural analysis sheds new light on the ligand binding activity of this functionally obscure but abundant human lipocalin.
Lehrstuhl für Biologische Chemie, Technische Universität München, D-85350 Freising-Weihenstephan, Germany.
Daniel A
DA
Breustedt
Ingo P
IP
Korndörfer
Bernhard
B
Redl
Arne
A
Skerra
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D054835:Lipocalin 1; D046911:Macromolecular Substances / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; C518443:LCN1 protein, human; D008024:Ligands; D054835:Lipocalin 1; D046911:Macromolecular Substances; D011480:Protease Inhibitors; D011994:Recombinant Proteins