Association of the kinesin-binding domain of RanBP2 to KIF5B and KIF5C determines mitochondria localization and function

Traffic. 2007 Dec;8(12):1722-35. doi: 10.1111/j.1600-0854.2007.00647.x. Epub 2007 Sep 21.

Abstract

The Ran-binding protein 2 (RanBP2) is a large mosaic protein with a pleiotropic role in cell function. Although the contribution of each partner and domain of RanBP2 to its biological functions are not understood, physiological deficits of RanBP2 downregulate glucose catabolism and energy homeostasis and lead to delocalization of mitochondria components in photosensory neurons. The kinesin-binding domain (KBD) of RanBP2 associates selectively in the central nervous system (CNS), and directly, with the ubiquitous and CNS-specific kinesins, KIF5B and KIF5C, respectively, but not with the highly homologous KIF5A. Here, we determine the molecular and biological bases of the selective interaction between RanBP2 and KIF5B/KIF5C. This interaction is conferred by a approximately 100-residue segment, comprising a portion of the coiled-coil and globular tail cargo-binding domains of KIF5B/KIF5C. A single residue conserved in KIF5B and KIF5C, but not KIF5A, confers KIF5-isotype-specific association with RanBP2. This interaction is also mediated by a conserved leucine-like heptad motif present in KIF5s and KBD of RanBP2. Selective inhibition of the interaction between KBD of RanBP2 and KIF5B/KIF5C in cell lines causes perinuclear clustering of mitochondria, but not of lysosomes, deficits in mitochondrial membrane potential and ultimately, cell shrinkage. Collectively, the data provide a rationale of the KIF5 subtype-specific interaction with RanBP2 and support a novel kinesin-dependent role of RanBP2 in mitochondria transport and function. The data also strengthen a model whereby the selection of a large array of cargoes for transport by a restricted number of motor proteins is mediated by adaptor proteins such as RanBP2.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Biological Transport
  • Cattle
  • Cell Nucleus / metabolism
  • Central Nervous System / metabolism
  • Gene Expression Regulation*
  • Humans
  • Kinesin / chemistry*
  • Kinesin / physiology
  • Lysosomes / metabolism
  • Mice
  • Mitochondria / metabolism*
  • Models, Biological
  • Molecular Chaperones / chemistry*
  • Molecular Chaperones / physiology
  • Molecular Sequence Data
  • Neurons / metabolism
  • Nuclear Pore Complex Proteins / chemistry*
  • Nuclear Pore Complex Proteins / physiology
  • Protein Binding
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Transfection
  • Two-Hybrid System Techniques

Substances

  • KIF5B protein, human
  • Molecular Chaperones
  • Nuclear Pore Complex Proteins
  • ran-binding protein 2
  • KIF5C protein, human
  • Kinesin