Homo sapiens (human)
An amyloid fibril is one from of aggregate of degraded fragments of unfolded proteins and is seen in diseases such as Alzheimer disease and dialysis-related amyloidosis (DRA). Amyloid fiber is highly stable and unusually resistant to dissociation or enzymatic degradation. All of the amyloid fibers have common characteristic structure called cross-beta sheet structure, whose strands run perpendicular to the fibril axis. Recent work demonstrated that the ability to form amyloid fibrils is not limited to proteins known to be associated with such diseases: several 'normal' proteins are found to be capable of self-associate into amyloid fibril. For example, the amyloid fiber found in DRA is consisting of beta-2-microglobulin (beta2m), which is a component of MHC class I molecules. Beta2m fibers are known to form only with the addition of Cu2+, which catalyses formation of intermediate called M* state. Conversion of native state to M* state is the initial step of beta2m amyloidosis, but structural information of this structural change had been lacking. Cu2+ is known to be bound in the vicinity of Pro32, which may cause change the cis conformation in Pro32 to trans conformation. The authors of this paper set up a hypothesis that backbone isomerization of Pro32 is responsible for conversion to M* state, and they solved the structure of the beta2m(P32A) mutant, which mimics M* state of beta2m.
The structure shown here is that of dimer of M* state-like beta2m (P32A). Beta2m has a seven-stranded beta-sandwich fold, one side of which is made by four-stranded sheets (A, B, E, and D) and another side of which is made by three-stranded sheets(C, F, and G). The dimer of P32A is mediated by anti-parallel interactions of two D strands. The authors of this paper indicated that the mutation at P32 induced rotations of backbone residues 52-56, result in loss of beta-bulge at Asp35 seen in the wild type and emergence of continuous strand D, which enables formation of a dimerization-competent interface.
Protein Data Bank (PDB)
author: Miho Higurashi