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Properties of some variants of human beta 2-microglobulin and amyloidogenesis
Three variants of human b2-microglobulin (beta 2-m) were compared to wild-type protein. For two variants, namely the mutant R3Abeta 2-m and the form devoid of the N-terminal tripeptide (DN3beta 2-m), a reduced unfolding free energy was measured compared to wild-type beta 2-m, whereas an increased stability was observed for the mutant H31Ybeta 2-m. The solution structure could be determined by 1H NMR spectroscopy and restrained modelling only for R3Abeta 2-m that showed the same conformation as the parent species, except for deviations at the interstrand loops. Analogous conclusions were reached for H31Ybeta 2-m and DN3beta 2-m. Precipitation and unfolding were observed over time periods shorter than 4-6 weeks with all the variants and, sometimes, with wild-type protein. The rate of structured protein loss from solution due to precipitation and unfolding always showed pseudo-zeroth order kinetics. This and the failure to observe an unfolded species without precipitation suggest that a nucleated conformational conversion scheme should apply for beta 2-m fibrillogenesis. The mechanism is consistent with the previous and present results on beta 2-m amyloid transition, provided a nucleated oligomeric species be considered the stable intermediate of fibrillogenesis, the monomeric intermediate being the necessary transition step along the pathway from the native protein to the nucleated oligomer.
Peer Reviewed Journal Article
J Biol Chem. 2004 Mar 5;279(10):9176-89.
Journal of Biological Chemistry
Corazza A, Pettirossi F, Viglino P, Verdone G, Garcia J, Dumy P, Giorgetti S, Mangione P, Raimondi S, Stoppini M, Bellotti V, Esposito G
Last updated on April 27, 2007
This work is supported in part by the Nanoscale Science and Engineering Initiative of the National Science Foundation
under NSF Award Number EEC-0118007.
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