Fe65-PTB2 Dimerization Mimics Fe65-APP Interaction
Physiological function and pathology of the Alzheimer’s disease causing amyloid precursor protein (APP) are correlated with its cytosolic adaptor Fe65 encompassing a WW and two phosphotyrosine-binding domains (PTBs). The C-terminal Fe65-PTB2 binds a large portion of the APP intracellular domain (AIC...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2017-05-01
|
| Series: | Frontiers in Molecular Neuroscience |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00140/full |
| _version_ | 1831771459725295616 |
|---|---|
| author | Lukas P. Feilen Kevin Haubrich Kevin Haubrich Paul Strecker Sabine Probst Simone Eggert Gunter Stier Irmgard Sinning Uwe Konietzko Stefan Kins Bernd Simon Klemens Wild |
| author_facet | Lukas P. Feilen Kevin Haubrich Kevin Haubrich Paul Strecker Sabine Probst Simone Eggert Gunter Stier Irmgard Sinning Uwe Konietzko Stefan Kins Bernd Simon Klemens Wild |
| author_sort | Lukas P. Feilen |
| collection | DOAJ |
| description | Physiological function and pathology of the Alzheimer’s disease causing amyloid precursor protein (APP) are correlated with its cytosolic adaptor Fe65 encompassing a WW and two phosphotyrosine-binding domains (PTBs). The C-terminal Fe65-PTB2 binds a large portion of the APP intracellular domain (AICD) including the GYENPTY internalization sequence fingerprint. AICD binding to Fe65-PTB2 opens an intra-molecular interaction causing a structural change and altering Fe65 activity. Here we show that in the absence of the AICD, Fe65-PTB2 forms a homodimer in solution and determine its crystal structure at 2.6 Å resolution. Dimerization involves the unwinding of a C-terminal α-helix that mimics binding of the AICD internalization sequence, thus shielding the hydrophobic binding pocket. Specific dimer formation is validated by nuclear magnetic resonance (NMR) techniques and cell-based analyses reveal that Fe65-PTB2 together with the WW domain are necessary and sufficient for dimerization. Together, our data demonstrate that Fe65 dimerizes via its APP interaction site, suggesting that besides intra- also intermolecular interactions between Fe65 molecules contribute to homeostatic regulation of APP mediated signaling. |
| first_indexed | 2024-12-22T07:59:41Z |
| format | Article |
| id | doaj.art-1f8fb131998b4e0886bb287a66fd4d8a |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-22T07:59:41Z |
| publishDate | 2017-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-1f8fb131998b4e0886bb287a66fd4d8a2022-12-21T18:33:17ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992017-05-011010.3389/fnmol.2017.00140262305Fe65-PTB2 Dimerization Mimics Fe65-APP InteractionLukas P. Feilen0Kevin Haubrich1Kevin Haubrich2Paul Strecker3Sabine Probst4Simone Eggert5Gunter Stier6Irmgard Sinning7Uwe Konietzko8Stefan Kins9Bernd Simon10Klemens Wild11Heidelberg University Biochemistry Center (BZH), University of HeidelbergHeidelberg, GermanyHeidelberg University Biochemistry Center (BZH), University of HeidelbergHeidelberg, GermanyEuropean Molecular Biology Laboratory (EMBL), Structural and Computational BiologyHeidelberg, GermanyDivision of Human Biology and Human Genetics, University of KaiserslauternKaiserslautern, GermanyInstitute for Regenerative Medicine (IREM), University of ZurichZurich, SwitzerlandDivision of Human Biology and Human Genetics, University of KaiserslauternKaiserslautern, GermanyHeidelberg University Biochemistry Center (BZH), University of HeidelbergHeidelberg, GermanyHeidelberg University Biochemistry Center (BZH), University of HeidelbergHeidelberg, GermanyInstitute for Regenerative Medicine (IREM), University of ZurichZurich, SwitzerlandDivision of Human Biology and Human Genetics, University of KaiserslauternKaiserslautern, GermanyEuropean Molecular Biology Laboratory (EMBL), Structural and Computational BiologyHeidelberg, GermanyHeidelberg University Biochemistry Center (BZH), University of HeidelbergHeidelberg, GermanyPhysiological function and pathology of the Alzheimer’s disease causing amyloid precursor protein (APP) are correlated with its cytosolic adaptor Fe65 encompassing a WW and two phosphotyrosine-binding domains (PTBs). The C-terminal Fe65-PTB2 binds a large portion of the APP intracellular domain (AICD) including the GYENPTY internalization sequence fingerprint. AICD binding to Fe65-PTB2 opens an intra-molecular interaction causing a structural change and altering Fe65 activity. Here we show that in the absence of the AICD, Fe65-PTB2 forms a homodimer in solution and determine its crystal structure at 2.6 Å resolution. Dimerization involves the unwinding of a C-terminal α-helix that mimics binding of the AICD internalization sequence, thus shielding the hydrophobic binding pocket. Specific dimer formation is validated by nuclear magnetic resonance (NMR) techniques and cell-based analyses reveal that Fe65-PTB2 together with the WW domain are necessary and sufficient for dimerization. Together, our data demonstrate that Fe65 dimerizes via its APP interaction site, suggesting that besides intra- also intermolecular interactions between Fe65 molecules contribute to homeostatic regulation of APP mediated signaling.http://journal.frontiersin.org/article/10.3389/fnmol.2017.00140/fullFe65phosphotyrosine-binding domain (PTB)homodimerizationamyloid precursor protein (APP)AICDAlzheimer’s disease |
| spellingShingle | Lukas P. Feilen Kevin Haubrich Kevin Haubrich Paul Strecker Sabine Probst Simone Eggert Gunter Stier Irmgard Sinning Uwe Konietzko Stefan Kins Bernd Simon Klemens Wild Fe65-PTB2 Dimerization Mimics Fe65-APP Interaction Frontiers in Molecular Neuroscience Fe65 phosphotyrosine-binding domain (PTB) homodimerization amyloid precursor protein (APP) AICD Alzheimer’s disease |
| title | Fe65-PTB2 Dimerization Mimics Fe65-APP Interaction |
| title_full | Fe65-PTB2 Dimerization Mimics Fe65-APP Interaction |
| title_fullStr | Fe65-PTB2 Dimerization Mimics Fe65-APP Interaction |
| title_full_unstemmed | Fe65-PTB2 Dimerization Mimics Fe65-APP Interaction |
| title_short | Fe65-PTB2 Dimerization Mimics Fe65-APP Interaction |
| title_sort | fe65 ptb2 dimerization mimics fe65 app interaction |
| topic | Fe65 phosphotyrosine-binding domain (PTB) homodimerization amyloid precursor protein (APP) AICD Alzheimer’s disease |
| url | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00140/full |
| work_keys_str_mv | AT lukaspfeilen fe65ptb2dimerizationmimicsfe65appinteraction AT kevinhaubrich fe65ptb2dimerizationmimicsfe65appinteraction AT kevinhaubrich fe65ptb2dimerizationmimicsfe65appinteraction AT paulstrecker fe65ptb2dimerizationmimicsfe65appinteraction AT sabineprobst fe65ptb2dimerizationmimicsfe65appinteraction AT simoneeggert fe65ptb2dimerizationmimicsfe65appinteraction AT gunterstier fe65ptb2dimerizationmimicsfe65appinteraction AT irmgardsinning fe65ptb2dimerizationmimicsfe65appinteraction AT uwekonietzko fe65ptb2dimerizationmimicsfe65appinteraction AT stefankins fe65ptb2dimerizationmimicsfe65appinteraction AT berndsimon fe65ptb2dimerizationmimicsfe65appinteraction AT klemenswild fe65ptb2dimerizationmimicsfe65appinteraction |