Pore-forming proteins share structural and functional homology with amyloid oligomers.
Degenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases are believed to be causally related to the accumulation of amyloid oligomers that exhibit a common structure and may be toxic by a common mechanism involving permeabilization of membranes. We discovered that amyloid oligomers and the pore-forming bacterial toxin, alpha-hemolysin (alpha HL), as well as human perforin from cytotoxic T lymphocytes, share a structural and functional homology at the level of their common reactivity with a conformation-dependent antibody that is specific for amyloid oligomers, A11. The alpha HL oligomeric pores and partially folded alpha HL protomer, but not the monomer alpha HL precursor reacts with A11 antibody. A11 antibody inhibits the hemolytic activity of alpha HL, indicating that the structural homology is functionally significant. Perforin oligomers were also recognized by A11. Amyloidogenic properties of alpha HL and perforin were confirmed spectroscopically and morphologically. These results indicate that pore forming proteins (PFP) and amyloid oligomers share structural homology and suggest that PFPs and amyloid oligomers share the same mechanism of membrane permeabilization.
Yoshiike
Yuji
Y
Laboratory for Alzheimer's Disease, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
Kayed
Rakez
R
Milton
Saskia C
SC
Takashima
Akihiko
A
Glabe
Charles G
CG
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000906:Antibodies / Q000276:immunology; D001427:Bacterial Toxins / Q000737:chemistry* / Q000302:isolation & purification; D003840:Deoxycholic Acid / Q000737:chemistry; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000302:isolation & purification; D006460:Hemolysin Proteins / Q000737:chemistry* / Q000302:isolation & purification; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry*; D054353:Perforin / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry
D016229:Amyloid beta-Peptides; D000906:Antibodies; D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; C036507:Hlya protein, E coli; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D003840:Deoxycholic Acid; D054353:Perforin