2F8O

A Native to Amyloidogenic Transition Regulated by a Backbone Trigger

Summary for 2F8O

• Entry DOI: 10.2210/pdb2f8o/pdb
• Descriptor: Beta-2-microglobulin (2 entities in total)
• Functional Keywords: beta-sandwich, amyloid, class-1 mhc, immune system
• Biological source: Homo sapiens (human)
• Cellular location: Secreted . Note=(Microbial infection) In the presence of M: P61769
• Total number of polymer chains: 2
• Total formula weight: 23706.64

Authors

Eakin, C.M.,Berman, A.J.,Miranker, A.D. (deposition date: 2005-12-02, release date: 2006-02-21, Last modification date: 2024-11-20)

Primary citation

Eakin, C.M.,Berman, A.J.,Miranker, A.D.
A native to amyloidogenic transition regulated by a backbone trigger.
Nat.Struct.Mol.Biol., 13:202-208, 2006

PubMed Abstract: Many polypeptides can self-associate into linear, aggregated assemblies termed amyloid fibers. High-resolution structural insights into the mechanism of fibrillogenesis are elusive owing to the transient and mixed oligomeric nature of assembly intermediates. Here, we report the conformational changes that initiate fiber formation by beta-2-microglobulin (beta2m) in dialysis-related amyloidosis. Access of beta2m to amyloidogenic conformations is catalyzed by selective binding of divalent cations. The chemical basis of this process was determined to be backbone isomerization of a conserved proline. On the basis of this finding, we designed a beta2m variant that closely adopts this intermediate state. The variant has kinetic, thermodynamic and catalytic properties consistent with its being a fibrillogenic intermediate of wild-type beta2m. Furthermore, it is stable and folded, enabling us to unambiguously determine the initiating conformational changes for amyloid assembly at atomic resolution.

PubMed: 16491088
DOI: 10.1038/nsmb1068

Experimental method

X-RAY DIFFRACTION (1.7 Å)