Abstract

The cytoskeleton-associated protein-glycine-rich domain (CAP-Gly; PF01302) is a small, approximately 80-residue protein module conserved in organisms from yeast to human. CAP-Gly domains have central functions in many proteins, including cytoplasmic linker proteins (CLIPs and CLIPRs), the large subunit of the dynactin complex (DCTN1, or p150glued), tubulin folding cofactors B and E, centrosome-associated protein-350 (CAP350), the kinesin protein KIF13b and the familial cylindromatosis tumor suppressor CYLD. These proteins are implicated in essential cellular processes such as chromosome segregation, establishment and maintenance of cell polarity, intracellular organelle and vesicle transport, cell migration, intracellular signaling and oncogenesis.

The CAP-Gly domains of microtubule-associated-proteins (MAPs) are characterized by the conserved GKNDG motif, which is responsible for targeting to the carboxy terminal EEY/F sequence motifs of CLIP-170, EB proteins, and alpha-tubulin. In addition to recognizing the terminal tyrosine the the CAP-Gly domains of CLIPs can also specifically recognize the preceding tryptophan residue of the C-terminal WxxGCY sequence motif of SLAINs.

The CAP-Gly EEY/F interaction is essential for the recruitment of the dynactin complex by CLIP170 (through p150glued) and for activation of CLIP-170. Furthermore, in most eukaryotic cells, the EEY/F tail of alpha-tubulin is subjected to an enzymatic detyrosination-tyrosination cycle in which the C-terminal tyrosine is repeatedly cleaved and added back. Suppression of this cycle leads to defects in spindle positioning, abnormal cell morphology, disorganized neuronal networks and tumour progression, underscoring the importance of this post-translational modification. Alpha-tubulin tyrosination has been linked to the ability of the microtubule plus end to recruit the CAP-Gly proteins p150glued, CLIP-170 and CLIP-115. Thus, the CAP-Gly-EEY/F interaction plays a fundamental role in the tubulin detyrosination-tyrosination cycle by controlling CAP-Gly proteins and as a consequence microtubule function.