TTC5 mediates autoregulation of tubulin via mRNA degradation

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Abstract

Tubulins play crucial roles in cell division, intracellular traffic, and cell shape. Tubulin concentration is autoregulated by feedback control of mRNA degradation via an unknown mechanism. Here, we identified tetratricopeptide protein 5 (TTC5) as a tubulin-specific ribosome-associating factor that triggers co-translational degradation of tubulin mRNAs in response to excess soluble tubulin. Structural analysis revealed that TTC5 binds near the ribosome exit tunnel and engages the N terminus of nascent tubulins. TTC5 mutants incapable of ribosome or nascent tubulin interaction abolished tubulin autoregulation and showed chromosome segregation defects during mitosis. Our findings show how a subset of mRNAs can be targeted for coordinated degradation by a specificity factor that recognizes the nascent polypeptides they encode.

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Dynamic instability of individual microtubules analyzed by video light microscopy: rate constants and transition frequencies

HP Erickson, D Salmon, ET O’Brien … (1988)

We have developed video microscopy methods to visualize the assembly and disassembly of individual microtubules at 33-ms intervals. Porcine brain tubulin, free of microtubule-associated proteins, was assembled onto axoneme fragments at 37 degrees C, and the dynamic behavior of the plus and minus ends of microtubules was analyzed for tubulin concentrations between 7 and 15.5 microM. Elongation and rapid shortening were distinctly different phases. At each end, the elongation phase was characterized by a second order association and a substantial first order dissociation reaction. Association rate constants were 8.9 and 4.3 microM-1 s-1 for the plus and minus ends, respectively; and the corresponding dissociation rate constants were 44 and 23 s-1. For both ends, the rate of tubulin dissociation equaled the rate of tubulin association at 5 microM. The rate of rapid shortening was similar at the two ends (plus = 733 s-1; minus = 915 s-1), and did not vary with tubulin concentration. Transitions between phases were abrupt and stochastic. As the tubulin concentration was increased, catastrophe frequency decreased at both ends, and rescue frequency increased dramatically at the minus end. This resulted in fewer rapid shortening phases at higher tubulin concentrations for both ends and shorter rapid shortening phases at the minus end. At each concentration, the frequency of catastrophe was slightly greater at the plus end, and the frequency of rescue was greater at the minus end. Our data demonstrate that microtubules assembled from pure tubulin undergo dynamic instability over a twofold range of tubulin concentrations, and that the dynamic instability of the plus and minus ends of microtubules can be significantly different. Our analysis indicates that this difference could produce treadmilling, and establishes general limits on the effectiveness of length redistribution as a measure of dynamic instability. Our results are consistent with the existence of a GTP cap during elongation, but are not consistent with existing GTP cap models.

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Mitotic spindle assembly in animal cells: a fine balancing act

Suzanna L. Prosser, Laurence Pelletier (2017)

Three microtubule nucleation pathways — initiated from centrosomes, chromatin and existing spindle microtubules — contribute to the assembly of a functional mitotic spindle in animal cells to ensure accurate chromosome segregation. Recent findings have shed light on their relative contributions to building the spindle and on adaptation of the spindle to variations in cell size and shape.

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Microtubule dynamics: an interplay of biochemistry and mechanics

Gary J. Brouhard, Luke Rice (2018)

Microtubules are dynamic polymers of αβ-tubulin that are essential for intracellular organization and chromosome segregation. Microtubule growth and shrinkage occur via addition and loss of αβ-tubulin subunits — biochemical processes. Dynamic microtubules can also exert forces by pushing or pulling against a load – mechanical processes. Recent advances at the intersection of biochemistry and mechanics have revealed the existence of multiple conformations of αβ-tubulin and their central role in dictating the mechanisms of microtubule dynamics and how microtubules do work. Microtubule associated proteins selectively target specific tubulin conformations to regulate microtubule dynamics, and mechanical forces can also influence microtubule dynamics by altering the balance of tubulin conformations. Importantly, the conformational states of tubulin dimers appear to be coupled throughout the lattice, in that the conformation of one dimer affects the conformation of its nearest neighbors and beyond. This coupling provides a long-range mechanism by which MAPs and forces can modulate microtubule growth and shrinkage. These findings provide evidence that the interplay between biochemistry and mechanics is essential for the cellular functions of microtubules.