Structural changes of region 1-16 of the Alzheimer disease amyloid beta-peptide upon zinc binding and in vitro aging.

Séverine Zirah (1) , Sergey A Kozin (1) , Alexey K Mazur (2) , Alain Blond (1) , Michel Cheminant (1) , Isabelle Ségalas-Milazzo , Pascale Debey (3) , Sylvie Rebuffat (1)

1 Laboratoire de chimie et biochimie des substances naturelles
2 IBPC (FR_550) - Institut de biologie physico-chimique
3 Régulation et dynamique des génomes

Amyloid deposits within the cerebral tissue constitute a characteristic lesion associated with Alzheimer disease. They mainly consist of the amyloid peptide Abeta and display an abnormal content in Zn(2+) ions, together with many truncated, isomerized, and racemized forms of Abeta. The region 1-16 of Abeta can be considered the minimal zinc-binding domain and contains two aspartates subject to protein aging. The influence of zinc binding and protein aging related modifications on the conformation of this region of Abeta is of importance given the potentiality of this domain to constitute a therapeutic target, especially for immunization approaches. In this study, we determined from NMR data the solution structure of the Abeta-(1-16)-Zn(2+) complex in aqueous solution at pH 6.5. The residues His(6), His(13), and His(14) and the Glu(11) carboxylate were identified as ligands that tetrahedrally coordinate the Zn(II) cation. In vitro aging experiments on Abeta-(1-16) led to the formation of truncated and isomerized species. The major isomer generated, Abeta-(1-16)-l-iso-Asp(7), displayed a local conformational change in the His(6)-Ser(8) region but kept a zinc binding propensity via a coordination mode involving l-iso-Asp(7). These results are discussed here with regard to Abeta fibrillogenesis and the potentiality of the region 1-16 of Abeta to be used as a therapeutic target.

Mots clés: ALZHEIMER DISEASE

Mots clés: PEPTIDE

Domaines: Biochimie, Biologie Moléculaire

Séverine Zirah, Sergey A Kozin, Alexey K Mazur, Alain Blond, Michel Cheminant, et al.. Structural changes of region 1-16 of the Alzheimer disease amyloid beta-peptide upon zinc binding and in vitro aging.. Journal of Biological Chemistry, 2006, 281 (4), pp.2151-61. ⟨10.1074/jbc.M504454200⟩. ⟨hal-00145835⟩