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3D domain‐swapped human cystatin C with amyloidlike intermolecular β‐sheets

Oligomerization of human cystatin C (HCC) leads to amyloid deposits in brain arteries, and this process is greatly accelerated with a naturally occurring L68Q variant. The crystal structures of N‐truncated and full‐length HCC (cubic form) showed dimer formation via three‐dimensional (3D) domain swapping, and this observation has led to the suggestion that an analogous domain‐swapping mechanism, but propagated in an open‐ended fashion, could be the basis of HCC fibril formation. Here we report that full‐length HCC, when crystallized in a new, tetragonal form, dimerizes by swapping the same secondary structure elements but with a very different overall structure generated by the flexibility of the hinge linking the moveable elements. The β‐strands of the β‐cores of the two folding units of the present dimer are roughly parallel, while they formed an angle of about 100° in the previous two structures. The dimers pack around a crystallographic dyad by extending their molecular β‐sheets in an intermolecular context. At the other edge of the molecular β‐sheet, side‐chain–side‐chain hydrogen bonds propagate the β‐structure in the same direction. In consequence, a supramolecular crystal structure is generated, with all the β‐strands of the domain‐swapped dimers being perpendicular to one crystallographic direction. This observation is relevant to amyloid aggregation of HCC, as X‐ray diffraction studies of amyloid fibrils show them to have ordered, repeating structure, consistent with the so‐called cross‐β structure, in which extended polypeptide chains are perpendicular to the fiber axis and form infinite β‐sheets that are parallel to this axis. Proteins 2005. © 2005 Wiley‐Liss, Inc.