Review of the chemistry of α_S2-casein and the generation of a homologous molecular model to explain its properties¹

The primary structure of α_S2-CN A-11P (Brignon et al., 1977 as modified by Farrell et al., 2004). Serine residues identified as phosphorylated (SeP) are indicated in bold italics.

Left: Trace of the backbone structure of α_S2-CN derived by homologous modeling. The amino acid sequence of α_S2-CN was threaded onto the model of CLIC-4. Right: Manipulation of Ala 116 to produce a hydrophobic core accessible for protein-protein interactions. Coiled ribbons represent α-helix, broad ribbons represent β-sheet, and arrowheads indicate the direction of travel of the chain from N- to C-terminal.

A) Stereo view of the Cα trace of the homologous model for α_S2-CN as given in Figure 2 (right panel); B) mono view of the energy-minimized model with backbone visible and ribboned for defined secondary structures (coiled ribbons represent α-helix, and broad ribbons represent β-sheet), and the free SH groups at residues 36 and 40 are indicated.

Pseudo charge surface representation of the α_S2-CN model. On the right the molecule is in the same orientation as in Figures 2 and 3. The negative charges (red) on the top left and center arise from the anionic sections of the molecule. The positive charges (blue) on the right arise from the C-terminal section of the molecule. The region extending from the center to 6 o’clock represents the central hydrophobic core; it is lightly colored and this section is free to react with other casein molecules as has been speculated for the homologous section of κ-CN (Kumosinski et al., 1994). The molecule on the left is rotated 90° clockwise displaying the C-terminal positively charged areas.

Tight loop introduced by the internal disulfide bond of α_S2-CN between Cys 36 and Cys 40. The disulfide bond lies between a stretch of helix and one of sheet. The Phe 39 side chain is shown as a point of reference.

Bioactive peptides from the C-terminal of α_S2-CN. A) Molecular model for the peptide fragment of α_S2-CN (Kizawa et al., 1996) homologous to calmodulin-binding protein domains f (183–207). In the model the latter segment is primarily composed of α-helix (residues 183–190, 194–199, and 204–207). The 3 sections of helix are separated by 2 nontraditional turns or tight loops. The overall structure can be characterized as an open hairpin; B) molecular model for α_S2-CN f (165–203) called casocidin I by Zucht et al. (1995). In this case the latter 2 sections of helix are again separated by a nontraditional turn or tight loop, but the first 2 are separated by a section of the molecule (172–180) that is linear in structure and is primarily in a polyproline II configuration (173–178). This makes the peptide quite planar with the overall appearance of a Greek letter Ω; C) molecular model for the major angiotensin I converting enzyme (ACE) inhibitor in tryptic digests of α_S2-CN f (174–181) (Tauzin et al., 2002). Residues 173–180 are in the polyproline II conformation.

Peptides from α_S2-CN potentially active in the intestine. A) Molecular model for the potential antiallergenic peptide from α_S2-CN f (102–111) as discovered by Tanabe et al. (2006). Note the tight helical conformation and the presence of Trp (bottom) and the segment as a potential β-sheet (top); B) molecular model for α_S2-CN f (34–59) as excised from the total model (right) and compared with the crystal structure (left) for defensin 6 (Szyk et al., 2006).