Lipocalins

The lipocalin protein family is a large group of small extracellular proteins which are characterized by common ligand-binding properties: they all bind small hydrophobic molecules (retinoids, arachidonic acid and steroids), specific cell-surface receptors and form complexes with soluble macromolecules (Flower 1996). The large degree of variation in amino-acid sequences found within the family may be consistent with the functional diversity found for these proteins. Thus, they participate in retinol transport, in invertebrate cryptic coloration, olfaction, and pheromone transport, prostaglandin synthesis, etc. (see Flower 1996, for a review).

Sequence comparison analyses have revealed the existence of three defining sequence motifs according to which two lipocalin subgroups can be identified: kernel and outlier lipocalins. Whereas kernel lipocalins share the three sequence motifs, the more divergent and in fact minor subgroup of outlier lipocalins matches no more than two. Concerning this, more recently, a classification of lipocalins has been proposed based on the three-dimensional superposition of the P-barrel fold (see below; Skerra 2000). On the other hand, analysis of available crystal structures of lipocalins, among others, plasma retinol-binding protein (RBP) (Newcomer et al. 1984; Cowan et al. 1990), P-lactoglobulin (Papiz et al. 1986; Monaco etal. 1987;Brownlowetal. 1997),insecticyanin (Holdenetal. 1987), a2u-globulin (Bocskei et al. 1992; Chaudhuri et al. 1999), epididymal retinoic acid-binding protein (Newcomer 1993), and odorant-binding protein (Tegoni et al. 1996; Bianchet et al. 1996), shows a highly conserved calyx-shaped fold composed of an eight-stranded antiparallel P-barrel with an elliptical cross-section and an internal ligand-binding cavity (Fig. 3.15) (Skerra 2000). In addition to the barrel scaffold, other conserved structural elements are: a single-turn 3i0 helix located in the N-terminal end, and a four-turn a-helix together with a small P-strand in the C-terminal end. The barrel topology is simple in that each successive strand is adjacent to the previous one, the last strand hydrogen bonding to the first one.

Membrane Lipocalin

ß-lactoglobulin a-2u-globul¡n

Odorant binding protein

Epididymal-FABP

Fig. 3.15. Gallery of ribbon structures of members from the lipocalin family. The conserved calyx-shaped fold Is composed of an eight-stranded antiparallel p-barrel with an internal llg-and-bindlng cavity. PDB codes are: 1IIU for the plasma retinol-binding protein (RBP); 1BEB, for p-lactoglobulln; 2A2U, for a2U-globulln; 1EPB, for epididymal fatty acid-binding protein; 1PBO, for the dlmer of the odorant-binding protein. The retlnol molecule bound to RBP, the retinoic acid bound to epidldymal-FABP, and the hydrophobic llgand of the odorant-binding proteln,appear as stick models. Figures were prepared with the program PyMOL

Whereas one end of the barrel, precisely that defining the base of the calyx, is capped by an amino-terminal sequence stretch and two short connecting loops (those between strands 02/03 and 06/07), the other end is open to the solvent, and conforms the entrance to the ligand-binding site. In this region, the unique longest connecting loop (loop between 01 and 02) acts as a lid which partially covers the ligand-binding site.

Lipocalins bind a great diversity of hydrophobic ligands: retinoids, pherom-ones, FAs, biliverdin, carotenoids, progesterone, prostaglandin H2, etc. (Flower 1996). In all structurally characterized cases, the ligand occupies the internal cavity of the barrel. For example, in the holo-RBP form, the 0-ionone ring of the ligand is bound deepest in the barrel, the isoprene chain is fully extended, and the hydroxyl group reaches the protein surface (Zanotti et al. 1994). Comparison of this last structure with that of the apo-RBP reveal the existence of conformational changes mainly affecting the above-mentioned lid segment (Zanotti et al. 1993).

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