title: A new Mint1 isoform, but not the conventional Mint1, interacts with the small GTPase Rab6.
abstract: Small GTPases of the Rab family are important regulators of a large variety of different cellular functions such as membrane organization and vesicle trafficking. They have been shown to play a role in several human diseases. One prominent member, Rab6, is thought to be involved in the development of Alzheimer's Disease, the most prevalent mental disorder worldwide. Previous studies have shown that Rab6 impairs the processing of the amyloid precursor protein (APP), which is cleaved to β-amyloid in brains of patients suffering from Alzheimer's Disease. Additionally, all three members of the Mint adaptor family are implied to participate in the amyloidogenic pathway. Here, we report the identification of a new Mint1 isoform in a yeast two-hybrid screening, Mint1 826, which lacks an eleven amino acid (aa) sequence in the conserved C-terminal region. Mint1 826, but not the conventional Mint1, interacts with Rab6 via the PTB domain. This interaction is nucleotide-dependent, Rab6-specific and influences the subcellular localization of Mint1 826. We were able to detect and sequence a corresponding proteolytic peptide derived from cellular Mint1 826 by mass spectrometry proving the absence of aa 495-505 and could show that the deletion does not influence the ability of this adaptor protein to interact with APP. Taking into account that APP interacts and co-localizes with Mint1 826 and is transported in Rab6 positive vesicles, our data suggest that Mint1 826 bridges APP to the small GTPase at distinct cellular sorting points, establishing Mint1 826 as an important player in regulation of APP trafficking and processing.
authors.affiliation: Department of Experimental Tumorbiology, University Muenster, Muenster, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Thyrock
authors.forename: Edith
authors.initials: E
authors.lastname: Ossendorf
authors.forename: Martin
authors.initials: M
authors.lastname: Stehling
authors.forename: Mark
authors.initials: M
authors.lastname: Kail
authors.forename: Tanja
authors.initials: T
authors.lastname: Kurtz
authors.forename: Gottfried
authors.initials: G
authors.lastname: Pohlentz
authors.forename: Dieter
authors.initials: D
authors.lastname: Waschbüsch
authors.forename: Simone
authors.initials: S
authors.lastname: Eggert
authors.forename: Etienne
authors.initials: E
authors.lastname: Formstecher
authors.forename: Johannes
authors.initials: J
authors.lastname: Müthing
authors.forename: Klaus
authors.initials: K
authors.lastname: Dreisewerd
authors.forename: Stefan
authors.initials: S
authors.lastname: Kins
authors.forename: Bruno
authors.initials: B
authors.lastname: Goud
authors.forename: Angelika
authors.initials: A
authors.lastname: Barnekow
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C094135:Rab6 protein; D020691:rab GTP-Binding Proteins