The GxxxG Motif in the Transmembrane Domain of A beta PP Plays an Essential Role in the Interaction of CTF beta with the gamma-secretase Complex and the Formation of Amyloid-beta

gamma-secretase-mediated processing of the amyloid-beta protein precursor (A beta PP) is a crucial step in the formation of the amyloid-beta peptide (A beta), but little is known about how the substrate A beta PP interacts with the gamma-secretase complex. To understand the molecular events involved in gamma-secretase-mediated A beta PP processing and A beta formation, in the present study we determined the role of a well conserved GxxxG motif in the transmembrane domain of A beta PP. Our data clearly demonstrate that substitution of aspartic acid for the key glycine residues in the GxxxG motif almost completely abolished the formation of A beta. Furthermore, our data revealed that substitution of aspartic acid for the glycine in this GxxxG motif disrupts the interaction of A beta PP with the gamma-secretase complex. Thus, the present study revealed an essential role for the GxxxG motif in the interaction of A beta PP with the gamma-secretase complex and the formation of A beta.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000269629500017&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701NeurosciencesSCI(E)4ARTICLE1167-1761