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Elucidation of primary structure elements controlling early amyloid beta-protein oligomerization.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Bitan, Gal Vollers, Sabrina S. Teplow, David B. |
| Copyright Year | 2003 |
| Abstract | Assembly of monomeric amyloid beta-protein (A beta) into oligomeric structures is an important pathogenetic feature of Alzheimer's disease. The oligomer size distributions of aggregate-free, low molecular weight A beta 40 and A beta 42 can be assessed quantitatively using the technique of photo-induced cross-linking of unmodified proteins. This approach revealed that low molecular weight A beta 40 is a mixture of monomer, dimer, trimer, and tetramer, in rapid equilibrium, whereas low molecular weight A beta 42 preferentially exists as pentamer/hexamer units (paranuclei), which self-associate to form larger oligomers. Here, photo-induced cross-linking of unmodified proteins was used to evaluate systematically the oligomerization of 34 physiologically relevant A beta alloforms, including those containing familial Alzheimer's disease-linked amino acid substitutions, naturally occurring N-terminal truncations, and modifications altering the charge, the hydrophobicity, or the conformation of the peptide. The most important structural feature controlling early oligomerization was the length of the C terminus. Specifically, the side-chain of residue 41 in A beta 42 was important both for effective formation of paranuclei and for self-association of paranuclei into larger oligomers. The side-chain of residue 42, and the C-terminal carboxyl group, affected paranucleus self-association. A beta 40 oligomerization was particularly sensitive to substitutions of Glu22 or Asp23 and to truncation of the N terminus, but not to substitutions of Phe19 or Ala21. A beta 42 oligomerization, in contrast, was largely unaffected by substitutions at positions 22 or 23 or by N-terminal truncations, but was affected significantly by substitutions of Phe19 or Ala21. These results reveal how specific regions and residues control A beta oligomerization and show that these controlling elements differ between A beta 40 and A beta 42. |
| Starting Page | 1 |
| Ending Page | 2 |
| Page Count | 2 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://faculty.neuroscience.ucla.edu/institution/publication-download?publication_id=113321 |
| Alternate Webpage(s) | http://people.healthsciences.ucla.edu/institution/publication-download?publication_id=113321 |
| Alternate Webpage(s) | https://cloudfront.escholarship.org/dist/prd/content/qt0w10568r/qt0w10568r.pdf |
| PubMed reference number | 12840029v1 |
| Volume Number | 278 |
| Issue Number | 37 |
| Journal | The Journal of biological chemistry |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Alzheimer's Disease Amino Acid Substitution Amino Acids Amyloid beta-Peptides Carboxyl Group Heparin, Low-Molecular-Weight Large Molecular Weight Protein Truncation Abnormality monomer newton procollagen Type I N-terminal peptide |
| Content Type | Text |
| Resource Type | Article |
