Two polymorphs of an independent amyloid core in medin's C- terminal region.

Medin, a 50-residue fragment of lactadherin (MFG-E8), forms aortic medial amyloid, the most common localized amyloid in humans, and co-deposits with vascular amyloid-β (Aβ) in Alzheimer's disease. In the full-length medin fibril the N-terminal half forms the entire protofilament interface, yet the strongest predicted amyloidogenic determinants lie in the C-terminal region. Here we show that this region aggregates on its own. The isolated C-terminal aggregation-prone region (medin C-APR, medin 31–53) begins to aggregate with the same lag time as full-length medin and assembles into two coexisting polymorphs, determined here by cryo-EM at 2.71 and 2.91 Å. Both are built from the same two-stranded β-arch and a pseudo-2 1 protofilament pair closed by an aromatic–aliphatic zipper, and differ only in how many accessory chains the exposed hydrophobic face recruits. The medin C-terminus therefore carries an amyloid core of its own, unrelated to that of the full-length fibril: medin has more than one aggregation-prone region, and the structural contribution of each region depends on sequence and assembly context.