Abstract：
:β-2-Microglobulin (β2m) forms amyloid fibrils in the joints of patients undergoing dialysis treatment as a result of kidney failure. One of the ways in which β2m can be induced to form amyloid fibrils in vitro is via incubation with stoichiometric amounts of Cu(II). To better understand the structural changes caused by Cu(II) binding that allow β2m to form amyloid fibrils, we compared the effect of Ni(II) and Zn(II) binding, which are two similarly sized divalent metal ions that do not induce β2m amyloid formation. Using hydrogen/deuterium exchange mass spectrometry (HDX/MS) and covalent labeling MS, we find that Ni(II) has little effect on β2m structure, despite binding in the same region of the protein as Cu(II). This observation indicates that subtle differences in the organization of residues around Cu(II) cause distant changes that are necessary for oligomerization and eventual amyloid formation. One key difference that we find is that only Cu(II), not Ni(II) or Zn(II), is able to cause the cis-trans isomerization of Pro32 that is an important conformational switch that initiates β2m amyloid formation. By comparing HDX/MS data from the three metal-β2m complexes, we also discover that increased dynamics in the β-sheet formed by the A, B, D, and E β strands of the protein and repositioning of residues in the D-E loop are necessary aspects of β2m forming an amyloid-competent dimer. Altogether, our results reveal new structural insights into the unique effect of Cu(II) in the metal-induced amyloid formation of β2m.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Borotto NB,Zhang Z,Dong J,Burant B,Vachet RWdoi
10.1021/acs.biochem.6b01198subject
Has Abstractpub_date
2017-02-28 00:00:00pages
1095-1104issue
8eissn
0006-2960issn
1520-4995journal_volume
56pub_type
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