Phosphorylation-independent dual-site binding of the FHA domain of KIF13 mediates phosphoinositide transport via centaurin alpha1

Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20346-51. doi: 10.1073/pnas.1009008107. Epub 2010 Nov 5.

Abstract

Phosphatidylinositol 3,4,5-triphosphate (PIP3) plays a key role in neuronal polarization and axon formation. PIP3-containing vesicles are transported to axon tips by the kinesin KIF13B via an adaptor protein, centaurin α1 (CENTA1). KIF13B interacts with CENTA1 through its forkhead-associated (FHA) domain. We solved the crystal structures of CENTA1 in ligand-free, KIF13B-FHA domain-bound, and PIP3 head group (IP4)-bound conformations, and the CENTA1/KIF13B-FHA/IP4 ternary complex. The first pleckstrin homology (PH) domain of CENTA1 specifically binds to PIP3, while the second binds to both PIP3 and phosphatidylinositol 3,4-biphosphate (PI(3,4)P(2)). The FHA domain of KIF13B interacts with the PH1 domain of one CENTA1 molecule and the ArfGAP domain of a second CENTA1 molecule in a threonine phosphorylation-independent fashion. We propose that full-length KIF13B and CENTA1 form heterotetramers that can bind four phosphoinositide molecules in the vesicle and transport it along the microtubule.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Axons / metabolism*
  • Biological Transport / physiology
  • Calorimetry
  • Chromatography, Affinity
  • Chromatography, Gel
  • Cloning, Molecular
  • Computational Biology
  • Crystallography
  • Electrophoresis, Polyacrylamide Gel
  • Glutathione Transferase
  • Humans
  • Kinesins / chemistry*
  • Kinesins / genetics
  • Kinesins / metabolism
  • Models, Chemical
  • Models, Molecular*
  • Mutagenesis, Site-Directed
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology*
  • Phosphatidylinositol Phosphates / metabolism*
  • Protein Conformation*
  • Transport Vesicles / metabolism

Substances

  • ADAP1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Nerve Tissue Proteins
  • Phosphatidylinositol Phosphates
  • phosphatidylinositol 3,4,5-triphosphate
  • Glutathione Transferase
  • KIF13B protein, human
  • Kinesins