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Volume 272, Number 1, Issue of January 3, 1997 pp. 58-62
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Binding of Amyloid  Protein to the 20 S Proteasome

(Received for publication, May 17, 1996, and in revised form, September 23, 1996)

From the Department of Psychiatry and Behavioral Science, School of Medicine, State University of New York, Stony Brook, New York 11794 and the ^§ Biology Department, Brookhaven National Laboratory, Upton, New York 11973

Neurodegenerative disorders of aging are characterized by the intraneuronal accumulation of ubiquitin conjugates into tangles and inclusions. Ubiquitin conjugates are degraded by cellular particles known as proteasomes. We have previously shown that amyloid  protein (A) inhibits proteasomal activity and thereby blocks ubiquitin conjugate degradation. In the present studies, we found that A binds the 20 S proteasome and forms a proteasome-A complex. The complex was detected by Western blot with anti-A antibodies. Using a 1.4 nm Nanogold-labeled A, we visualized proteasome-A complexes by scanning transmission electron microscopy (STEM). Analysis of the side-on oriented proteasome-A complexes revealed a single gold particle, corresponding to one gold-labeled A, in the middle portion of the proteasome. On end-on views of proteasome-A complexes, gold was detected within the area delimited by the proteasome circular projection. Both STEM views are consistent with A localization inside the proteasome along the peptide channel. Direct interaction of A with the inner catalytic compartment of the proteasome may explain the generation of ubiquitin-containing lesions in Alzheimer's disease and other neurodegenerative disorders. In addition, detection of Nanogold-labeled peptide inside the 20 S eukaryotic proteasome suggests that conformational constraints for protein degradation in eukaryotic proteasomes are different from those in archaebacteria proteasomes.

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