Molecular Cell
Volume 23, Issue 5, 1 September 2006, Pages 663-671
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Article
Key Interaction Modes of Dynamic +TIP Networks

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Summary

Dynamic microtubule plus-end tracking protein (+TIP) networks are implicated in all functions of microtubules, but the molecular determinants of their interactions are largely unknown. Here, we have explored key binding modes of +TIPs by analyzing the interactions between selected CAP-Gly, EB-like, and carboxy-terminal EEY/F-COO sequence motifs. X-ray crystallography and biophysical binding studies demonstrate that the β2-β3 loop of CAP-Gly domains determines EB-like motif binding specificity. They further show how CAP-Gly domains serve as recognition domains for EEY/F-COO motifs, which represent characteristic and functionally important sequence elements in EB, CLIP-170, and α-tubulin. Our findings provide a molecular basis for understanding the modular interaction modes between α-tubulin, CLIPs, EB proteins, and the dynactin-dynein motor complex and suggest that multiple low-affinity binding sites in different combinations control dynamic +TIP networks at microtubule ends. They further offer insights into the structural consequences of genetic CAP-Gly domain defects found in severe human disorders.

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