Unique effect of Cu(II) in the metal-induced amyloid formation of β-2-microglobulin.
β-2-Microglobulin (β2m) forms amyloid fibrils in the joints of patients undergoing hemodialysis treatment as a result of kidney failure. In the presence of stoichiometric amounts of Cu(II), β2m self-associates into discrete oligomeric species, including dimers, tetramers, and hexamers, before ultimately forming amyloid fibrils that contain no copper. To improve our understanding of whether Cu(II) is unique in its ability to induce β2m amyloid formation and to delineate the coordinative interactions that allow Cu(II) to exert its effect, we have examined the binding of Ni(II) and Zn(II) to β2m and the resulting influence that these metals have on β2m aggregation. We find that, in contrast to Cu(II), Ni(II) does not induce the oligomerization or aggregation of β2m, while Zn(II) promotes oligomerization but not amyloid fibril formation. Using X-ray absorption spectroscopy and new mass spectrometry-related techniques, we find that different binding modes are responsible for the different effects of Ni(II) and Zn(II). By comparing the binding modes of Cu(II) with Ni(II), we find that Cu(II) binding to Asp59 and the backbone amide between the first two residues of β2m are important for allowing the formation of amyloid-competent oligomers, as Ni(II) appears not to bind these sites on the protein. The oligomers formed in the presence of Zn(II) are permitted by this metal's ability to bridge two β2m units via His51. These oligomers, however, are not able to progress to form amyloid fibrils because Zn(II) does not induce the required structural changes near the N-terminus and His31.
Department of Chemistry, University of Massachusetts , Amherst, Massachusetts 01003, United States.
Jia
J
Dong
Crisjoe A
CA
Joseph
Nicholas B
NB
Borotto
Vanessa L
VL
Gill
Michael J
MJ
Maroney
Richard W
RW
Vachet
D000682:Amyloid / Q000737:chemistry*; D003300:Copper / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009532:Nickel / Q000378:metabolism / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects*; D017433:Protein Structure, Secondary; D013379:Substrate Specificity; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000378:metabolism*
D000682:Amyloid; D001613:beta 2-Microglobulin; D003300:Copper; D009532:Nickel; D015032:Zinc