Human beta two microglobulin: Difference between revisions

up to 60-fold, giving rise to pathogenic accumulation of filamentous structures, displaying the  

typical properties of amyloid fibrils, principally in the joints and connective tissue.

==Monomeric human b2m (Mhb2m)==

The first crystal structure of Monomeric human b2m (Mhb2m) is solved in 2002 (pdb 1LDS). The protein is 99 residue in length and has a seven-stranded β sandwich fold typical of the Immunoglobulin superfamily. It is stabilized by a single disulfide bond between  

</StructureSection>

=Amyloid Fibril formation of Mhb2m=

==Mhb2m fiber formation conditions==

In separate studies b2m has been shown to form oligomers and fibrils at neutral pH by addition of Cu2+ and 1 M urea. This induces the formation of a non-native species, called M*, that appears identical to IT by size exclusion chromatography (SEC). Coordination of the metal ion promotes peptide bond isomerisation at Pro32, and the subsequent rapid formation of oligomers as

judged by SEC, providing further supporting evidence that the isomerisation of Pro32 is a key initial step on the pathway to fibrils.Structural studies of the trapped folding intermediate, IT (orM*), have provided molecular insights into the possible aggregation mechanisms of b2m at neutral pH. For example, crystallographic data for the mutant, P32A shows that this conformer results in substantial reorganisation of aromatic side-chains that are present in the core of the native protein. In this structure, a number of aromatic and hydrophobic residues are displaced including Phe30, Phe56, Trp60, Phe62, Tyr63 and Leu54. These rearrangements present a strip of exposed hydrophobic residues on the protein surface, providing a possible avenue for protein aggregation (Fig.3). This species crystallises as a dimer underlining its potential to form intermolecular interactions.

==Fibrillar architecture==

In aqueous solution at neutral or acidic condition, amyloid-like fibrils are formed from b2m that show a long-straight, left-hand twisted and unbranched morphology when observed by EM and AFM (Fig.4)

===A unifying mechanism of b2m fibril formation===

to a similar fibrillar product. This could occur by unfolding of native b2m to allow reorganisation of the protein structure; or by

refolding of the highly dynamic polypeptide chain at pH 2.5 to a more structurally ordered intermediate species (Fig.5).  

Similarities between the assembly mechanisms are supported by several reasons：