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USA 68,1130-1134 The structural motif of [3- lactoglobulin and retinol-binding protein: a basic framework for binding and transport of small hydrophobic molecules? Jasminka Godovac-Zimmermann The recently revealed homology of the primary structures of [blactoglobulin, retinol-binding protein, apolipoprotein 19, a-l-microglobulin and BG protein from olfactory epithelium, suggests the existence of a new protein superfamily of hydrophobic molecule transporters. The common protein fold of ~lactoglobulin, retinol-binding protein and bilin-binding protein must be particularly suitable for binding of various hydrophobic iigands of small molecular mass. Organisms make widespread use of small hydrophobic molecules such as steroids, retinoids, bilins and lipids. The insolubility of such molecules in water must lead to specific problems for an organism, but as yet relatively little is known about the mechanisms by which recognition, transport or regulation are achieved. Perhaps the best characterized system for transport of small hydro- phobic molecules is that of retinol. It is known that a specific protein (retinol- binding protein) is used to transport retinol in blood~ and that other proteins seem to be necessary to load retinol- binding protein with retinol in the liver2 and to release retinol in the target tis- sue3. An economical solution to nature's problem of how to recognize and/or transport small hydrophobic molecules would be the use of a common protein structural framework which could be J. Godovac-Zimmermann is at the Department of Biochemistry, John Curt& School of Medical Research, Australian National University, Canberra, A. C. T. 2601, Australia. modified to give the selectivity necessary for different ligands. There is increasing evidence that nature may have used exactly this approach and that a protein supeffamily whose function is binding and/or transport of small hydrophobic molecules does in fact exist. Recent results from X-ray crystallography and protein sequence determinations suggest this family may have functions as diverse as transport in the blood of retinol, cholesterol esters and bilins, as well as olfaction, sperm maturation and control of morphogens in milk. Retinol-binding protein- the first member of the superfamily The fact that retinol is transported in blood bound to retinol-binding protein has been known for some time. As the first member of this protein supeffamily to be described, this protein is quite well characterized. A variety of studies of function and genetics have been carded out and both the primary structure 4 and a three-dimensional structure s have been determined. When the three- dimensional structure was determined in ~) 1988. Elsevier Publications Cambridge 0376- 5067188/$02.00 1984, retinol-binding protein rep- resented a new type of protein architec- ture and it was immediately suggested that it might represent a new protein superfamily5. Surprisingly, the second member of this protein superfamily to be identified, in 1985, was ~-lactogiobulinr, 7. Although this protein was first isolated from milk whey as long as 50 years ago, its biological function remained unknown (for a recent review, see Ref. 8). Over the past several years, the primary struc- tures of nine 13-1actoglobulins from dif- ferent species have been determined 9-1~. The sequence homology between these [~-lactoglobufins and retinol-bind- ing protein suggested a common molecu- lar origin and a possible function for [I- lactoglobulin in binding and transport of retinol; [I-lactoglobulin is known to bind retinollS. The inclusion of ~-lactogiobulin in the supeffamily has since been con- firmed by the three-dimensional struc- ture of this protein, which has a very similar folding pattern to retinol-binding proteinT, 19. Very recently, the three- dimensional structure of a third member of this protein supeffamily, bilin-binding protein, has also been determind20, 21. Although the protein fold of bilin-bind- ing protein is very similar to that of other members of the supeffamily, the ligand specificity is very different and suggests that, with appropriate modification of the primary structure, this protein family may be able to bind a wide variety of dif- ferent hydrophobic ligands. The architecture of this protein super- family appears to be highly appropriate for binding of a variety of hydrophobic ligands. The protein fold consists of a 13- barrel formed by two orthogonal [I- sheets and an a-helix (see Fig. 1). Ligands are bound within the central cavity of the ~-barrel and it seems entirely possible that, by changing the residue types in the central cavity, rather different ligand specificity could be