Apolipoprotein domain structure

Saito, H., Lund-Katz, S., Phillips, M.C. 2004. Contributions of domain structure and lipid interaction to the functionality of exchangeable human apolipoproteins. Prog. Lipid Res. 43 350-380. 

FIGURE 3 The domain structure of a plasma lipoprotein. The nonpolar lipids triglyceride and cholesterol ester are surrounded by the amphipathic lipids phospholipid and cholesterol. The latter are stabilized by apolipoproteins. These proteins have amphipathic a-helix and amphipathic y6-sheet secondary structures. 

H41. Huby, T., Doucet, C., Dieplinger, H., Chapman, J., and Thillet, J., Structural domains of apolipoprotein(a) and its interaction with apolipoprotein Bl00 in the lipoprotein(a) particle. Biochemistry 33, 3335-3341 (1994). 

Fig. 9. RNA editing, (a) Unedited apolipoprotein B mRNA is translated to yield ApoB-100, a 4536-amino acid long polypeptide with structural domains for lipoprotein assembly and receptor binding functions (b) translation of the edited mRNA yields the shorter ApoB-48 which lacks the receptor binding domain.

Apolipoprotein C-II can also be isolated from VLDL or HDL (H20, L5, N3). It contains 78 residues (J3) and has been shown by Chou-Fasman analysis to bind phospholipids (M26, M40), with three predicted helical sequences (M26). ApoC-II has attracted a great deal of attention because it activates one of the most important enzymes in plasma lipid metabolism, lipoprotein lipase, responsible for the hydrolysis of triglyceride in chylomicrons and VLDL. Sparrow and Gotto have summarized a number of studies on structure-function relationships (S52). These, taken together, indicate that there are separate functional domains in apoC-II, in that lipoprotein lipase activation is mediated by residues 55-78 and phospholipid binding by... 

C. Wilson, M.R. Warded, K.H. Weisgraber, R.W. Mahley, and D.A. Agard. 1991. Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E Science 252 1817-1822. (PubMed)... 

In humans, apoA-IV is found primarily in the free protein (nonlipoprotein) portion of plasma. Although the reason is not clear, it is possible that the lack of class A motif in the amphipathic helical domains of human apoA-IV causes it to associate poorly with the lipoprotein surface. In rats, however, apoA-IV is seen on HDLs. Examination of individual amphipathic helical domains of rat apoA-IV does show the presence of the class A motif in its structure, thus supporting our hypothesis that the class A motif is essential for binding of apolipoproteins to lipoproteins. 

Fig. 4. Crystal structures of human apolipoproteins in the lipid-free state. (A) The six a-helices in human apo A1 are shown (H.M.K. Murthy, 2006). The N-terminal anti-parallel four-helix bundle contains helices A (residues 10-39), B (50-84), C (97-137), and D (146-187). The C-terminal domain is formed by the two a-helices E (residues 196-213) and F (219-242). Hydrophobic residues located in the interior of the helix bundles are shown as sticks. (B) Ribbon model of the structure of the 22-kDa N-terminal domain fragment of human apo E3 (D.A. Agard, 1991). Four of the five helices are arranged in an anti-parallel four-helix bundle. The residues spanned by each helix, together with the region in helix 4 recognized by the LDL receptor, are indicated.

While lipoproteins are the products of many different genes, the major apolipoproteins share properties distinguishing them from most lipid-free and membrane-associated proteins. For example, apolipoproteins consist of a single polypeptide chain that has relatively little tertiary structure. Most apolipoproteins contain stretches of amphipathic alpha-helix, whose hydrophobic face can be turned to the lipid surface of the particle. The apolipoproteins are flexible, as is reflected in their unusually small free energy of unfolding. As these apolipoproteins expand and contract at the cell surface, different protein domains are exposed that are detectable with monoclonal antibodies. These properties reflect the role of apolipoproteins at the surface of lipoprotein particles whose size changes as they circulate. 

The cammon features of plasma lipoprotein structure are shown in Fig. 2. The interior of the lipoproteins contains the neutral lipids, cholesteryl ester and triglyceride. The exterior surface is a monomolecular film of specific proteins, termed apolipopro-teins, and the polar lipids, phosphatidylcholine and cholesterol. One possible arrangement (Edelstein et al., 1979) of the phosphatidylcholine, cholesterol and apolipoprotein A-1 (apoA-1) in HDL the most abundant of the plasma lipoproteins, is illustrated schematically in Fig. 3. In this model, there are no lipid domains in the surface of HDL. The phospholipid molecules are widely dispersed so that intermolecular associations can involve only apoprotein lipid and apoprotein apoprotein interactions. By contrast, with increasing size and a greater proportion of hydrophobic core volume, the structure of the larger lipoproteins more closely re-... 

Fig. 3. Topology of surface components of HDL. The cross-hatched areas represent the phospholipid polar head group, while the solid eliptical areas represent cholesterol. This scheme depicts two adjacent molecules of apoA-1 spread as a monomolecular film on the lipoprotein surface with phospholipid molecules interspersed between the structural domains of the apolipoprotein. (Edelstein et al., 1979, used with permission).

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