Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex.

Abstract

The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.

• Authors: Zhuangfeng Weng, Yuan Shang, Deqiang Yao, Jinwei Zhu, Rongguang Zhang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 1 Pg. 215-225 (01 05 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 29158259 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• Cytoskeletal Proteins
• KANK1 protein, human
• KIF21A protein, human
• Kank1 protein, mouse
• Kif21a protein, mouse
• Multiprotein Complexes
• Tumor Suppressor Proteins
• Kinesins

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Ankyrin Repeat
• Carrier Proteins (chemistry, genetics, metabolism)
• Crystallography, X-Ray
• Cytoskeletal Proteins
• Humans
• Kinesins (chemistry, genetics, metabolism)
• Mice
• Microtubules (metabolism)
• Multiprotein Complexes
• Mutation, Missense
• Protein Conformation, alpha-Helical
• Structure-Activity Relationship
• Tumor Suppressor Proteins (chemistry, genetics, metabolism)