Abstract
Tubulin-binding TOG domains are found arrayed in a number of proteins that regulate microtubule dynamics. While much is known about the structure and function of TOG domains in the XMAP215 microtubule polymerase family, less in known about the TOG domain array found in the CLASP family. The CLASP TOG array promotes microtubule pause, potentiates rescue, and limits catastrophe. How distinct the TOG domains of CLASP are from one another, from XMAP215 TOG domains, and whether they are positionally conserved across CLASP family members is poorly understood. We present the x-ray crystal structures of human CLASP1 TOG1 and TOG2. The structures of CLASP1 TOG1 and TOG2 are distinct from each other, from CLASP TOG3, and are positionally conserved across species. While studies have failed to detect CLASP TOG1 tubulin-binding activity, TOG1 is structurally similar to the free-tubulin binding TOG domains of XMAP215. In contrast, though CLASP TOG2 and TOG3 have tubulin binding activity, they are structurally distinct from the free-tubulin binding TOG domains of XMAP215. CLASP TOG2 has a convex architecture, predicted to engage a hyper-curved tubulin state. CLASP TOG3 has unique structural elements in the C-terminal half of its α-solenoid domain that modeling studies implicate in binding to laterally-associated tubulin subunits in the microtubule lattice in a mode similar to, yet distinct from XMAP215 TOG4. These findings highlight the structural diversity of TOG domains within the CLASP TOG array and provide a molecular foundation for understanding CLASP-dependent effects on microtubule dynamics.
