MAPping tubulin mutations

Abstract

Microtubules are filamentous structures that play a critical role in a diverse array of cellular functions including, mitosis, nuclear translocation, trafficking of organelles and cell shape. They are composed of α/β-tubulin heterodimers which are encoded by a large multigene family that has been implicated in an umbrella of disease states collectively known as the tubulinopathies. De novo mutations in different tubulin genes are known to cause lissencephaly, microcephaly, polymicrogyria, motor neuron disease, and female infertility. The diverse clinical features associated with these maladies have been attributed to the expression pattern of individual tubulin genes, as well as their distinct Functional repertoire. Recent studies, however, have highlighted the impact of tubulin mutations on microtubule-associated proteins (MAPs). MAPs can be classified according to their effect on microtubules and include polymer stabilizers (e.g., tau, MAP2, doublecortin), destabilizers (e.g., spastin, katanin), plus-end binding proteins (e.g., EB1-3, XMAP215, CLASPs) and motor proteins (e.g., dyneins, kinesins). In this review we analyse mutation-specific disease mechanisms that influence MAP binding and their phenotypic consequences, and discuss methods by which we can exploit genetic variation to identify novel MAPs.

Artificial Intelligence-Enabled AlphaFold II Pipeline Guides Functional Fluorescence Labeling of Tubulin Across Species

“…Next, we assessed the performance of the GFP11-i labeling approach on structural-sensitive tubulin variants harboring missense mutations, as these variants are analogous to disease-related mutated tubulins (Cushion et al, 2023). Specifically, we examined a ciliary tubulin isotype, α-tubulin TBA-5, which is predominantly localized in the distal segments of cilia within the sensory neurons of C. elegans .…”

“…To examine the applicability of GFP11-i labeling across multiple species, we extended this technique to human α-tubulin isotype hTUBA1A, β-tubulin hTUBB8 and mouse α-tubulin TUBA4A (Fig. 1 D), all of which had been implicated in tubulinopathies (Cushion et al, 2023). Equivalent quantities of CMV promotor-driven gfp-htuba1a or htuba1a (gfp11-i) constructs were transiently transfected into HeLa cell lines along with GFP1-10, individually (Fig.…”

“…Mutations in tubulin-coding genes are intrinsically associated with human diseases collectively designated as tubulinopathies such as cortical malformations, manifesting as microcephaly, lissencephaly or polymicrogyria (Cushion et al, 2023; Magiera et al, 2018; Tischfield et al, 2011). The symptomatic spectrum of tubulinopathies extends from severe intellectual deficits to nuanced cognitive impairments, accentuating the indispensable role of tubulins in cerebral ontogeny (Tischfield et al, 2011).…”

“…S1 A) (Cheng et al, 2023; Vakiani and Solit, 2011). Comprehensive exploration of the functional specificities among divergent wild-type and mutant tubulin isotypes holds the promise of elucidating the underlying pathophysiological mechanisms (Cushion et al, 2023), thereby facilitating the development of therapeutic strategies. Therefore, there is an imminent requirement to monitor the dynamics of individual tubulin isotypes in both wild-type and pathological forms.…”

ACLASP1variant suggests a phenotypic relation with lissencephaly in humans

“…CLASP1 belongs to a group of proteins known as CLASPs. These proteins are highly expressed in the central nervous system and are non-motor microtubule-associated proteins that interact with CLIPs, a member of the microtubule plus-end tracking protein family that promotes the stabilization of dynamic microtubules in migrating cells (Cushion, 2023). Loss of the CLASP1 C-terminus weakness MT plus-end binding.…”