Negative Design of SOD1

Amyloid fibers, associated with many diseases [75], are extremely stable entities made up of many ^-strands aligned perpendicular to the fiber axis [114]. Due to the fact that they already contain ^-sheets, P-proteins are constantly under evolutionary pressure to avoid the formation of amyloid fibers. Nature has addressed this issue by integrating structural elements into P-proteins that protect the edge strands of P-sheets from nonproductive self-associative interactions. This protection has been termed 'negative design' [115]. P-barrel formation is one example of how proteins have incorporated negative design elements to prevent self-association at edge strands. Other ways P proteins protect their P-sheet edges include covering them with loops or other structural elements, dimeriza-tion, and the introduction of P-bulges, proline residues, and strategically placed charged amino acids [115]. Loss of this protection through mutation can result in edge-strand interactions leading to oligomerization.

As shown in Figure 4, although SOD1 is classified as a P-barrel, each monomer is actually more like a P-sandwich that contains two sets of edge strands. The negative design of SOD1 comes both from its dimerization, protecting edge strands 1 and 8 (Figure 1A), and from well-ordered zinc and electrostatic loop elements that protect strands 5 and 6 (boxed in the left subunit of Figure 4). Dissociation of SOD1 or conformational mobility of the zinc and electrostatic loop elements could render the molecule vulnerable to self-association and/or aggregation with other proteins (see below).

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