Tubulin Folding and Degradation

Abstract

Synthesis of polypeptides inside a cell is an astonishing, complex and very efficient process. To reach the active state, proteins will have to face many different problems that in part are solved by molecular chaperones. Tubulins belong to one of the largest superfamilies of proteins with six conserved members. Different members have different roles although they share a general fold. Tubulins reach their final structure in an intricate pathway where different molecular chaperones are involved. Prefoldin and cytosolic chaperonin containing TCP1/TriC are required in the first part of the pathway, while tubulin folding cofactors (TBCs) are involved in the formation of the α‐ and β‐tubulin heterodimers. Later, their role in tubulin proteostasis as well as their implications in different neurodevelopmental disorders has been documented. Key Concepts Tubulins represent one of the largest families of genes and proteins. α‐ and β‐Tubulin heterodimers constitute the structural and functional subunit of microtubules (MTs). Folding of tubulins follows a sophisticated pathway involving several molecular chaperones. Formation of the αβ‐tubulin heterodimer is an extremely regulated process for it is involved in different lateral and longitudinal as well as microtubule associated proteins (MAPs) interactions. TBCs are molecular chaperones specifically required for αβ‐tubulin dimer formation. TBCs are shown to be involved in the release of tubulin monomers from the chaperonin during the folding pathway. The dissociation constant for the tubulin heterodimer has shown to be 10 −11 M and TBCs are required for an efficient tubulin dimer dissociation. TBCs are involved in tubulin proteostasis through dimer dissociation and tagging for proteasome recognition. The first 3D structure of a complex formed between α‐tubulin and two chaperones involved in the tubulin turnover cycle has been established. Genetic defects on TBCs are responsible of neurodevelopmental diseases.

Tau Structures

“…α and β subunits are folded independently with the GTP bound to each one. Among all the chaperones involved, including CCT and prefoldin, tubulin folding cofactors are molecular chaperones specifically required for αβ-tubulin dimer formation and the acquisition of its quaternary structure (Serna and Zabala, 2016). …”

Colchicine Blocks Tubulin Heterodimer Recycling by Tubulin Cofactors TBCA, TBCB, and TBCE

“…The dissociation complex may also be involved in α-tubulin degradation. The UBL domains of TBCE and TBCB present a protruding arrangement suggesting the possibility of interacting with the proteasome (Serna et al, 2015), as mechanistically detailed in the review by Serna and Zabala (2016).…”

“…This analysis was based on the fact that the tubulin dimer dissociation by TBCB/TBCE involves a ternary complex TBCE/TBCB/α-tubulin (Carranza et al, 2013;Serna et al, 2015). TBCE and TBCB have a cytoskeletonassociated protein glycine-rich (CAP-Gly) and a UBL domain (Grynberg et al, 2003;Serna and Zabala, 2016). The TBCB intermediate region has a short coiled-coil region (CC), whereas that of TBCE has a leucine-rich repeat (LRR) domain.…”

“…The overexpression of TBCD and TBCE completely disrupts the MT cytoskeleton (Martín et al, 2000;Kortazar et al, 2006). TBCD and TBCE are capable of dissociating the tubulin heterodimer by themselves, but in the case of TBCE, its dissociation activity is highly increased by the presence of TBCB (Serna and Zabala, 2016). In fact, TBCB and TBCE stabilize the α-tubulin subunit after dimer dissociation originating a ternary complex TBCE/TBCB/α-tubulin (Carranza et al, 2013;Serna et al, 2015).…”

“…In fact, TBCB and TBCE stabilize the α-tubulin subunit after dimer dissociation originating a ternary complex TBCE/TBCB/α-tubulin (Carranza et al, 2013;Serna et al, 2015). Both TBCB and TBCE share a CAP-Gly and a UBL (ubiquitin-like) domain in their primary structures, but in inverted order (Serna and Zabala, 2016). The dissociation complex may also be involved in α-tubulin degradation.…”