Abstract
The cancer-associated, centrosomal adaptor protein TACC3 (transforming acidic coiled-coil 3) and its direct effector, the microtubule polymerase chTOG (colonic and hepatic tumor overexpressed gene), play a crucial function in centrosome-driven mitotic spindle assembly. It is unclear how TACC3 interacts with chTOG. Here, we show that the C-terminal TACC domain of TACC3 and a C-terminal fragment adjacent to the TOG domains of chTOG mediate the interaction between these two proteins. Interestingly, the TACC domain consists of two functionally distinct subdomains, CC1 (amino acids (aa) 414-530) and CC2 (aa 530-630). Whereas CC1 is responsible for the interaction with chTOG, CC2 performs an intradomain interaction with the central repeat region of TACC3, thereby masking the TACC domain before effector binding. Contrary to previous findings, our data clearly demonstrate that Aurora-A kinase does not regulate TACC3-chTOG complex formation, indicating that Aurora-A solely functions as a recruitment factor for the TACC3-chTOG complex to centrosomes and proximal mitotic spindles. We identified with CC1 and CC2, two functionally diverse modules within the TACC domain of TACC3 that modulate and mediate, respectively, TACC3 interaction with chTOG required for spindle assembly and microtubule dynamics during mitotic cell division.
Highlights
The TACC3-chTOG protein complex is essential for mitotic spindle assembly
Coiled-coil prediction analysis indicated the presence of one breaking region that divides the C-terminal TACC domain of mammalian TACC3 proteins into two coiled-coil-containing subdomains, CC1 and CC2
That is exemplified by the embryonic lethality caused by TACC3 deficiency, which is not observed for TACC2 deficiency [37, 38, 40], as well as by the selective interaction of the aryl hydrocarbon receptor nuclear translocator (ARNT) with TACC3 but not with TACC1 and TACC2 [66]
Summary
The TACC3-chTOG protein complex is essential for mitotic spindle assembly. Results: TACC3-chTOG binding is directed and mediated by specific intradomain and interdomain interactions that are not affected by Aurora-A kinase. The cancer-associated, centrosomal adaptor protein TACC3 (transforming acidic coiled-coil 3) and its direct effector, the microtubule polymerase chTOG (colonic and hepatic tumor overexpressed gene), play a crucial function in centrosomedriven mitotic spindle assembly. It is unclear how TACC3 interacts with chTOG. That modulate and mediate, respectively, TACC3 interaction with chTOG required for spindle assembly and microtubule dynamics during mitotic cell division. Cancer cells e.g. counteract extra centrosomes and, the danger of multipolar divisions and excess aneuploidy/cell death through centrosome clustering [13,14,15] This process became an attractive pharmacological tumor target [16, 17]. Recent work by the Mitocheck consortium [25, 26] provided a global confirmation of known and identification of novel cell division genes and their protein
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