title: Polar transmembrane-based amino acids in presenilin 1 are involved in endoplasmic reticulum localization, Pen2 protein binding, and γ-secretase complex stabilization.
abstract: γ-Secretase is composed of the four membrane proteins presenilin, nicastrin, Pen2, and Aph1. These four proteins assemble in a coordinated and regulated manner into a high molecular weight complex. The subunits constitute a total of 19 transmembrane domains (TMD), with many carrying important amino acids involved in catalytic activity, interaction with other subunits, or in ER retention/retrieval of unassembled subunits. We here focus on TMD4 of presenilin 1 (PS1) and show that a number of polar amino acids are critical for γ-secretase assembly and function. An asparagine, a threonine, and an aspartate form a polar interface important for endoplasmic reticulum retention/retrieval. A single asparagine in TMD4 of PS1 is involved in a protein-protein interaction by binding to another asparagine in Pen2. Intriguingly, a charged aspartate in TMD4 is critical for γ-secretase activity, most likely by stabilizing the newly formed complex.
authors.affiliation: Leibniz Institut für Altersforschung-Fritz Lipmann Institut, 07743 Jena, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fassler
authors.affiliation: Leibniz Institut für Altersforschung-Fritz Lipmann Institut, 07743 Jena, Germany.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Li
authors.affiliation: Leibniz Institut für Altersforschung-Fritz Lipmann Institut, 07743 Jena, Germany. Electronic address: ckaether@fli-leibniz.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kaether
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D001216:Asparagine / Q000737:chemistry; D001665:Binding Sites; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D053764:Presenilin-1 / Q000737:chemistry / Q000378:metabolism*; D053766:Presenilin-2 / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D000596:Amino Acids; D053764:Presenilin-1; D053766:Presenilin-2; D001216:Asparagine