title: Conserved Lysine Acetylation within the Microtubule-Binding Domain Regulates MAP2/Tau Family Members.
abstract: Lysine acetylation has emerged as a dominant post-translational modification (PTM) regulating tau proteins in Alzheimer's disease (AD) and related tauopathies. Mass spectrometry studies indicate that tau acetylation sites cluster within the microtubule-binding region (MTBR), a region that is highly conserved among tau, MAP2, and MAP4 family members, implying that acetylation could represent a conserved regulatory mechanism for MAPs beyond tau. Here, we combined mass spectrometry, biochemical assays, and cell-based approaches to demonstrate that the tau family members MAP2 and MAP4 are also subject to reversible acetylation. We identify a cluster of lysines in the MAP2 and MAP4 MTBR that undergo CBP-catalyzed acetylation, many of which are conserved in tau. Similar to tau, MAP2 acetylation can occur in a cysteine-dependent auto-regulatory manner in the presence of acetyl-CoA. Furthermore, tubulin reduced MAP2 acetylation, suggesting tubulin binding dictates MAP acetylation status. Taken together, these results uncover a striking conservation of MAP2/Tau family post-translational modifications that could expand our understanding of the dynamic mechanisms regulating microtubules.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Hwang
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Hanna
authors.initials: H
authors.lastname: Trzeciakiewicz
authors.affiliation: Department of Biochemistry and Biophysics, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Dave
authors.initials: D
authors.lastname: Friedmann
authors.affiliation: Alexion Pharmaceuticals Inc, New Haven, Connecticut, United States of America.
authors.forename: Chao-Xing
authors.initials: CX
authors.lastname: Yuan
authors.affiliation: Department of Biochemistry and Biophysics, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Neurology, UNC Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Cohen
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000032:analysis; D011485:Protein Binding; D000072417:Protein Domains; D011499:Protein Processing, Post-Translational; D016415:Sequence Alignment; D053719:Tandem Mass Spectrometry; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D010455:Peptides; D014404:Tubulin; D016875:tau Proteins; D008239:Lysine