title: GDP-to-GTP exchange on the microtubule end can contribute to the frequency of catastrophe.
abstract: Microtubules are dynamic polymers of αβ-tubulin that have essential roles in chromosome segregation and organization of the cytoplasm. Catastrophe-the switch from growing to shrinking-occurs when a microtubule loses its stabilizing GTP cap. Recent evidence indicates that the nucleotide on the microtubule end controls how tightly an incoming subunit will be bound (trans-acting GTP), but most current models do not incorporate this information. We implemented trans-acting GTP into a computational model for microtubule dynamics. In simulations, growing microtubules often exposed terminal GDP-bound subunits without undergoing catastrophe. Transient GDP exposure on the growing plus end slowed elongation by reducing the number of favorable binding sites on the microtubule end. Slower elongation led to erosion of the GTP cap and an increase in the frequency of catastrophe. Allowing GDP-to-GTP exchange on terminal subunits in simulations mitigated these effects. Using mutant αβ-tubulin or modified GTP, we showed experimentally that a more readily exchangeable nucleotide led to less frequent catastrophe. Current models for microtubule dynamics do not account for GDP-to-GTP exchange on the growing microtubule end, so our findings provide a new way of thinking about the molecular events that initiate catastrophe.
authors.affiliation: Departments of Biophysics and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Felipe-Andrés
authors.initials: FA
authors.lastname: Piedra
authors.affiliation: Departments of Biophysics and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Tae
authors.initials: T
authors.lastname: Kim
authors.affiliation: Departments of Biophysics and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Garza
authors.affiliation: Departments of Biophysics and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Geyer
authors.affiliation: Departments of Biophysics and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Alexander
authors.initials: A
authors.lastname: Burns
authors.affiliation: Departments of Biophysics and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Xuecheng
authors.initials: X
authors.lastname: Ye
authors.affiliation: Departments of Biophysics and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390 Luke.Rice@UTSouthwestern.edu.
authors.forename: Luke M
authors.initials: LM
authors.lastname: Rice
mesh_terms: D048429:Cell Size; D003198:Computer Simulation; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism* / Q000502:physiology; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014404:Tubulin / Q000378:metabolism*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D014404:Tubulin; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate