The tubulin code and its role in controlling microtubule properties and functions

Abstract

Microtubules are core components of the eukaryotic cytoskeleton with essential roles in cell division, shaping, intracellular transport, and motility. Despite their functional heterogeneity, microtubules have a highly conserved structure made from almost identical molecular building blocks; the tubulin proteins. Alternative tubulin isotypes and a variety of posttranslational modifications control the properties and functions of the microtubule cytoskeleton, a concept known as the 'tubulin code'. This concept first emerged with the discovery that α-and β-tubulin are each encoded by multiple genes, but it took decades before its functional importance begun to emerge. Here we review the current understanding of the molecular components of the tubulin code, and how they impact microtubule properties and functions. We discuss how tubulin isotypes and posttranslational modifications control microtubule behaviour at the molecular level, and how this translates into physiological functions at the cellular and organism levels. We further show how the fine-tuning of microtubule functions by some tubulin modifications affects homeostasis, and how its perturbation can lead to a large variety of dysfunctions, many of them linked to human disorders.

The Mechanism of Tubulin Assembly into Microtubules: Insights from Structural Studies

“…At least two additional outstanding challenges remain for the understanding of the structural mechanism of microtubule function. The first one concerns tubulin's PTMs ( Janke and Magiera, 2020 ; Roll-Mecak, 2020 ). Many tubulin-modifying enzymes have been identified, and their structure, either isolated or bound to inhibitors or to tubulin peptides, has been determined.…”

“…Despite the high degree of conservation across species ( Little et al., 1981 ), a variety of tubulin molecules can be found in a single organism. Indeed, nine genes code for the α chain and nine genes code for the β chain in humans ( Janke and Magiera, 2020 ; Roll-Mecak, 2020 ). In addition to isotypic heterogeneity, which results directly from a genetic contribution, post-translational modifications (PTMs) of tubulin have been described.…”

“…For instance, acetylation takes place on Lys 40 of α-tubulin ( L'Hernault and Rosenbaum, 1985 ) and the acetyl group may then be removed ( Hubbert et al., 2002 ). The combination of the differential expression of α- and β-tubulin genes and of the PTMs collectively define a “tubulin code” conferring specialized functions to the microtubule cytoskeleton ( Janke and Magiera, 2020 ; Roll-Mecak, 2020 ).…”

Tubulin acetylation increases cytoskeletal stiffness to regulate mechanotransduction in striated muscle

“…This pathologic excess of microtubule dependent mechanotransduction manifested in increased susceptibility to contraction induced injury in skeletal muscle and a predisposition to arrhythmic events in the heart 8 . Here the focus has been on functionaltering post-translational modifications (PTMs) of α-tubulin by acetylation and detyrosination 9 .…”

“…Microtubules are dynamic polymers of α-β protein dimers where detyrosination (deTyrMT) or acetylation (acetylMT) increases filament longevity and binding [9][10][11][12] . In striated muscle both deTyrMT and acetylMT are evident in healthy cardiac and skeletal muscle and both are dramatically elevated in elevated in disease.…”