Conserved and Functionally Important Molecular Interactions

Although the Fc hinge region binding proteins are unrelated at the secondary and tertiary structural levels, patterns do emerge when one compares the detailed atomic interactions made by these molecules. Superposition of the available crystal structures enables identification of a set of conserved molecular interaction sites in the consensus region (Fig. 4). Although the overall folds of each of these Fc binding domains are distinct, there are numerous similarities in the geometric arrangements of the specific functional groups presented by each partner (Fig. 5).

Mutagenesis experiments with the Fc binding partners also support the notion that the consensus binding site serves as a shared "affinity handle" across the different receptors. FcRn binding can be disrupted by alanine substi-tions at positions 252, 253, 435, and 436 [2]. Likewise, the

Figure 5 Comparison of the Fc binding interactions of (a) the Fc binding peptide, (b) domain C2 from protein G, (c) rheumatoid factor, and (d) domain B1 of protein A. Numbers indicate the following conversed interactions: (1) salt bridges with His433, (2) hydrogen bonding to Asn434, (3) hydrophobic packing onto His435, (4) burial of the hydrophobic "knob" formed by Ile253 and Ser254, (5) hydrogen bonding to main chain (N-H) of Ile253, (6) hydrogen packing onto Met252 and Tyr436, (7) hydrogen bonding to Ser254, (8) salt bridges with Glu380, and (9) salt bridges with Arg255. For clarity, only interfacial atoms are shown, and only nitrogen and oxygen atoms involved in conserved polar interactions are colored blue or red, respectively. The remaining contacts are colored yellow and green. (Adapted from DeLano et al., Science, 287, 1279-1283, 2000. With permission.)

Figure 5 Comparison of the Fc binding interactions of (a) the Fc binding peptide, (b) domain C2 from protein G, (c) rheumatoid factor, and (d) domain B1 of protein A. Numbers indicate the following conversed interactions: (1) salt bridges with His433, (2) hydrogen bonding to Asn434, (3) hydrophobic packing onto His435, (4) burial of the hydrophobic "knob" formed by Ile253 and Ser254, (5) hydrogen bonding to main chain (N-H) of Ile253, (6) hydrogen packing onto Met252 and Tyr436, (7) hydrogen bonding to Ser254, (8) salt bridges with Glu380, and (9) salt bridges with Arg255. For clarity, only interfacial atoms are shown, and only nitrogen and oxygen atoms involved in conserved polar interactions are colored blue or red, respectively. The remaining contacts are colored yellow and green. (Adapted from DeLano et al., Science, 287, 1279-1283, 2000. With permission.)

Figure 4 Topology of converserved interaction sites in consensus binding region on Fc. The predominantly hydrophobic consensus region is shaded. The hydrogen bonding sites are shown with diagonal lines, and salt bridging locations are denoted by open circles. Nitrogen and oxygen are colored blue or red, respectively, and carbon and sulfur atoms are colored green. Hydrogens are not shown. (Adapted from DeLano et al., Science, 287, 1279-1283, 2000. With permission.)

Figure 4 Topology of converserved interaction sites in consensus binding region on Fc. The predominantly hydrophobic consensus region is shaded. The hydrogen bonding sites are shown with diagonal lines, and salt bridging locations are denoted by open circles. Nitrogen and oxygen are colored blue or red, respectively, and carbon and sulfur atoms are colored green. Hydrogens are not shown. (Adapted from DeLano et al., Science, 287, 1279-1283, 2000. With permission.)

binding of many rheumatoid factors is sensitive to truncation of the side-chain atoms in the consensus binding region [11,25]. Binding of protein A is disrupted by alanine substi-tions at positions 253 and 435, and the Fc binding peptide can be blocked by alanine substitutions at 434, 435, or 436 [8]. In each case, there are functionally important binding interactions in the consensus region, though the relative importance of individual residues appears to be non-uniform.

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