The mechanism through which globular proteins transform into amyloid fibrils is still not understood. Here we analyze the structure and sequence conservation to assess the differential stability of segments from two structurally related protein families: the amyloidogenic gelsolin-like and its structurally related cofilin-like. The two families belong to the actin depolymerizing proteins, with a central β-sheet stacked between 2 and 4 α-helices. Although sequentially remote, the two families share regions of high and low conservation and stability. Our results show a highly conserved hydrophobic and aromatic cluster, located at a central buried β-hairpin. The geometry of the aromatic residues with respect to each other is strictly conserved, suggesting involvement in strand registering and β-sheet stabilization. Consistent with experiment, we find a region of weak conservation and stability at one of the exposed β-strands (strand B in the gelsolin-like family). This region was recently found to be affected by a point mutation-mediated destabilization of the human gelsolin domain 2, which facilitates the first proteolytic event in the formation of the amyloidogenic fragment. Thus, both experimental and computational conservation analyses suggest that this unstable region may constitute a first step in amyloid formation. Our analysis uses a recently developed multiple-structure comparison algorithm in which molecules are aligned simultaneously.
- Sequence and structure conservation
- β-sheet stability