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The Intriguing Dynamics of C-Termini in Neuronal Microtubules: Unraveling the Brain's Cytoskeleton Function

This study delves into the role of the C-termini in microtubules within dendrites, shedding light on the brain's cytoskeleton function. It discusses the integration of various molecular and membrane levels, focusing on dendritic plasticity during learning. The study explores a model of the microtubule network and various dynamics of microtubules in neurons, highlighting their structural and functional significance. The potential implications for neuronal signaling and information processing are also discussed.

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The Intriguing Dynamics of C-Termini in Neuronal Microtubules: Unraveling the Brain's Cytoskeleton Function

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  1. The Dynamics of C-termini of Microtubules in Dendrites:A possible clue for the role of neuronal cytoskeleton in the functioning of the brain Jack Tuszynski Department of Physics University of Alberta Edmonton, Canada

  2. Acknowledgements • Avner Priel, Bar Ilan U/Univ of Alberta • Nancy Woolf, UCLA • Eric Carpenter • Tyler Luchko • Horacio Cantiello, Harvard Med School • Stephanie Portet, U Toronto Funding: NSERC, MITACS, YeTaDel, Technology Innovations LLC

  3. Motivation • Pyramidal cells collect O(105) inputs • Most of the computational tasks occur in the dendritic arbor • Dendrites are capable of non-trivial computation

  4. Microtubules in neurons

  5. Cytoskeletal structures in dendrites

  6. Challenge: integration of various levels Building a bridge between • the molecular level (cytoskeleton) • the membranelevel (synaptic activity, AP)

  7. Dendrites undergo significant structural plasticity during learning phases • Spine level changes • Cytoskeletal changes

  8. A MT tree in a dendritic forest

  9. Processivity kinesin ncd

  10. MT Binding Site of Kinesin Role of C-termini

  11. The Model MTN – Microtubule Network • A model of a single MT • Tubulin dimers interact electrically via dipole – dipole interactions • A model of the MAP • Elastic rod connected at both ends to adjacent MTs • MAP – MT interaction • Mechanical (elastic forces)

  12. MTN Dynamics

  13. Microtubules (MT) • lengths vary, but commonly reach 5–10 µm • usually 13 protofilaments in vivo • 12–17 protofilaments when self-assembled in vitro • protofilaments are strongly bound internally • protein filaments of the cytoskeleton

  14. Microtubules in dendrites : • Self-assemble to extend dendrites (and axons) • Form synaptic connections • Linked to ion-channels and synaptic receptors • Organized in parallel structures – interconnected by MAP-2 • Appear in mixed polarity

  15. Individual MT life story: dynamic instability • Catastrophes • Rescues • Growth phase • Shrinking phase Simulation using a recursive map

  16. Molecular Dynamics (MD) • class of model system • point masses (atoms) • simple forces • bond stretching, • Coulomb, • van der Waals, etc. • Newtonian integration over time

  17. Tubulin… • two major types of tubulin (a, b) pair in dimers • tubulin dimers are basic unit • dimers form protofilaments(vertical columns) • dimers form cylindrical microtubules (MTs)

  18. Electric Potential • slice through dimer • red/blue by potential strength • green isopotential lines • not well replaced with multipole expansion

  19. Protein Surface Potential • surface mix of positive (blue) and negative (red) charge regions • isopotential surface in yellow • note folded C-terminii

  20. C-termini • highly variable sequences • strongly electro-negative • having up to 10 netnegative charges • highly mobile, andunstructured region • electrostatic interactionwith nearby charges

  21. RMSF & RMSD (work in progress) • RMS fluctuations are a measure of the flexibility of a structure. • RMS deviations measure the change between two static structures. Created with VMD [Humphrey et al., 1996]

  22. Reconstruction of tubulin isotype structures including C-termini Green=alphaTBA 2 human Yellow=alpha 1TUB Red=alpha TBA4 human

  23. Effects of pH C-termini are antenna-like

  24. MT2 MAP MT1 The C-termini are key degrees of freedom

  25. Charge distribution of tubulin dimer including C-termini. Blue=negative Red=positive White=neutral Approx. 25 e per monomer or 50 per dimer

  26. Blue=negative chargeRed=positive chargeGreen=MAP binding region

  27. Conformational states of C-termini Up-up Up-down Down-down

  28. C-terminal–BodyInteractions • section of MT with 9 dimers • C-termini (not shown) can fold down onto (red) groove on dimer • very fast in MD simulations

  29. Local potential for C-termini orientations Well depth= several kT

  30. The proposed model to be developed: • The C-termini as the key degrees of freedom • Each C- terminus can be in one of several states: • up – extending outward from the surface • down – bound to the surface of a MT • Transitions between the states are induced by thermal fluctuations, interaction with neighboring C-termini and interference from adjacent MT’s mediated by the MAP • Transitions may induce ionic waves between MT’s and down the dendrite

  31. C-terminal Interactions • neighbouring C-termini • adjacent protein including • kinesin • MAPs (microtubule associated proteins) • adjacent surface of dimers

  32. MD simulation of C-termini conformations

  33. Collective states • Condition for an ordered state: zJ<kT => at T=300 K we get kT=25 meV Hence even J=5 meV with z=6 neighbors (hexatic lattice) leads to an ordered state where pair-wise interactions are below thermal noise This corresponds to f=6 10 12 Hz (MW) Possibly dipole-dipole or H-bond interactions

  34. Ionic Wave Propagation • RLC representation of a biopolymer from the view point of counterions • Speeds of 1-100 m/s possible • Localized traveling waves • Singaling • C-termini may collapse

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