title: Tau mediates microtubule bundle architectures mimicking fascicles of microtubules found in the axon initial segment.
abstract: Tau, an intrinsically disordered protein confined to neuronal axons, binds to and regulates microtubule dynamics. Although there have been observations of string-like microtubule fascicles in the axon initial segment (AIS) and hexagonal bundles in neurite-like processes in non-neuronal cells overexpressing Tau, cell-free reconstitutions have not replicated either geometry. Here we map out the energy landscape of Tau-mediated, GTP-dependent 'active' microtubule bundles at 37 °C, as revealed by synchrotron SAXS and TEM. Widely spaced bundles (wall-to-wall distance Dw-w≈25-41 nm) with hexagonal and string-like symmetry are observed, the latter mimicking bundles found in the AIS. A second energy minimum (Dw-w≈16-23 nm) is revealed under osmotic pressure. The wide spacing results from a balance between repulsive forces, due to Tau's projection domain (PD), and a stabilizing sum of transient sub-kBT cationic/anionic charge-charge attractions mediated by weakly penetrating opposing PDs. This landscape would be significantly affected by charge-altering modifications of Tau associated with neurodegeneration.
authors.affiliation: Materials Department, Physics Department, Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, California 93106, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Chung
authors.affiliation: Materials Department, Physics Department, Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, California 93106, USA.
authors.forename: Chaeyeon
authors.initials: C
authors.lastname: Song
authors.affiliation: Chemistry and Biochemistry Department, University of California, Santa Barbara, California 93106, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Deek
authors.affiliation: Neuroscience Research Institute and Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, California 93106, USA.
authors.forename: Herbert P
authors.initials: HP
authors.lastname: Miller
authors.affiliation: Materials Research Laboratory, University of California, Santa Barbara, California 93106, USA.
authors.forename: Youli
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
authors.forename: Myung Chul
authors.initials: MC
authors.lastname: Choi
authors.affiliation: Neuroscience Research Institute and Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, California 93106, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Wilson
authors.affiliation: Neuroscience Research Institute and Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, California 93106, USA.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Feinstein
authors.affiliation: Materials Department, Physics Department, Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, California 93106, USA.
authors.forename: Cyrus R
authors.initials: CR
authors.lastname: Safinya
mesh_terms: D000818:Animals; D000071040:Axon Initial Segment / Q000378:metabolism* / Q000648:ultrastructure; D002417:Cattle; D008870:Microtubules / Q000378:metabolism* / Q000648:ultrastructure; D009997:Osmotic Pressure; D000072417:Protein Domains; D053838:Scattering, Small Angle; D013816:Thermodynamics; D014961:X-Ray Diffraction; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016875:tau Proteins