Hinge loops of the RNase A major dimer...

Figure 2: Structure of the hinge loops of the RNase A major dimer, with implications for amyloid fiber formation. a, Structure of the open interface of the RNase A major dimer, showing the atomic structure for residues 110–117 of both molecules of the dimer. These segments correspond to the central portion of Figure 1. Carbon, nitrogen, and oxygen atoms are in yellow, blue, and red, respectively. Hydrogen bonds are shown as purple dots. Three hydrogen bonds are formed between Asn 113 residues in the two hinge loops. The atoms involved in these three hydrogen bonds are labeled. The figure is plotted with SETOR.

b, Speculative three-dimensional domain-swapping, polar-zipper model for formation of aggregates, with polyamide expansion loops. With the expansion of polyglutamine (PolyGln) in the hinge loop between two domains, a fluctuation that breaks the noncovalent bonds between the two domains exposes the polyglutamine loop as well as the two halves of the closed interface. The polyamide segment is able to form a b sheet, with three hydrogen bonds per residue pair, as observed for residue 113 in a. This stabilized sheet grows as additional polyamide b strands are added, defining the fiber axis perpendicular to the b strands, shown at the right. The sheet may be further stabilized by three-dimensional domain swapping formed by additional closed interfaces at the two sides of the sheet. A less-stable sheet could be formed by other (nonpolyamide) sequences and could account for the observation that proteins that undergo transition to the amyloid state exhibit enhanced b structure.