Intracellular Lipid Binding Proteins

Since the description of the first cellular fatty acid-binding protein (FABP) (Ockner et al. 1972), different types of iLBPs have been reported from various organisms and tissues (Hanhoff et al. 2002; Zimmerman and Veerkamp 2002; Haunerland and Spener 2004). Although much effort has been spent in elucidating the specific roles of iLBPs, this issue has thus far not been fully explored. Accordingly, various functions have been proposed for iLBPs, including not only uptake and transport of FAs, but also regulation of gene expression and cell growth (Haunerland and Spener 2004). A remarkable feature of the iLBPs family is that despite the high degree of sequence diversity and ligand binding properties observed, they share a common three-dimensional fold (Fig. 3.16).

All iLBPs consist of a ten-stranded antiparallel 0-barrel with an internal lig-and-binding cavity lined by both polar and apolar residues together with tightly bound water molecules (Banaszak et al. 1994; Thompson et al. 1997). In addition, a helix-turn-helix motif, which covers the opening of the barrel, together with two connecting loops (those between strands 0C and 0D, and 0E and 0F), has been postulated to function as a lid or flap (Hanhoff et al. 2002). Generally, one or two basic residues located within the cavity are directly involved in ligand binding; conversely, the hydrocarbon tail of the ligand is lined on one side by hydrophobic side-chains and the other with ordered water molecules. Four major subfamilies have been considered within the iLBPs based on sequence homology and lipid binding properties (Haunerland and Spener 2004): subfamily I comprises proteins specific for vitamin A derivatives: cellular retinoic acid-binding proteins (CRABP-I and II), and the cellular retinol-binding proteins (CRBP-I, II, III and IV) (Ross 1993); subfamily II is composed of proteins with larger binding sites which can accommodate not only different FAs but also heme, bile acids and certain eicosanoids. Members from this subfamily are liver-FABP (L-FABP), intestinal bile acid-binding protein (I-BABP), and also the basic liver-type (Lb-FABP), which is the only iLBP that is not expressed in mammals; it is found in

Fig.3.16. Structures ofsome members of the intracellular Iipid-bind-Ing proteins. ILBPs consist ofa ten-stranded antlparallel p-barrel with an internal llgand-bindlng cavity.

CRBP

Liver FA8P

Fig.3.16. Structures ofsome members of the intracellular Iipid-bind-Ing proteins. ILBPs consist ofa ten-stranded antlparallel p-barrel with an internal llgand-bindlng cavity.

PDB codes are: 1CRB for the complex between the cellular retlnol-blnding protein and retlnol; 1LFO,for liver

CRBP

Liver FA8P

FABP complexed with two mole

Intestinal FABP

Brain FABP

cules of oleate; 1ICM, intestinal FABP with bound myrlstate,and IFDQfor brain FABP. Bound llgands appear as stick models. Figures were prepared with the program PyMOL

Intestinal FABP

Brain FABP

the liver of birds, fishes, reptiles and amphibians (Di Pietro et al. 1999). It is remarkable that L-FABP is the only FABP that forms a ternary complex with two fatty acid molecules (Thompson et al. 1997). The only member of the subfamily

III is the intestinal type FABP (I-FABP). This protein is rather peculiar in both sequence and ligand binding properties. In this sense, the bound FA adopts a bent conformation, with the carboxylate moiety located deep inside the barrel cavity, interacting with an arginine residue (Sacchettini et al. 1992). Finally, subfamily

IV includes among others, FABPs from heart (H-FABP) (Lassen et al. 1995), adipocyte (A-FABP) (Ringom et al. 2004), epidermal (E-FABP) (Hohoff et al. 1999), myelin (M-FABP), testis (T-FABP) and brain (B-FABP) (Balendiran et al. 2000). These last proteins, which have an extra 3i0-helical loop in the N-terminal end when compared to the iLBPs, are characterized because the acyl chain of the ligand adopts a U-shape conformation.

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