Phosphorylation of KLC1 modifies interaction with JIP1 and abolishes the enhanced fast velocity of APP transport by kinesin-1

Mol Biol Cell. 2017 Dec 15;28(26):3857-3869. doi: 10.1091/mbc.E17-05-0303. Epub 2017 Nov 1.

Abstract

In neurons, amyloid β-protein precursor (APP) is transported by binding to kinesin-1, mediated by JNK-interacting protein 1b (JIP1b), which generates the enhanced fast velocity (EFV) and efficient high frequency (EHF) of APP anterograde transport. Previously, we showed that EFV requires conventional interaction between the JIP1b C-terminal region and the kinesin light chain 1 (KLC1) tetratricopeptide repeat, whereas EHF requires a novel interaction between the central region of JIP1b and the coiled-coil domain of KLC1. We found that phosphorylatable Thr466 of KLC1 regulates the conventional interaction with JIP1b. Substitution of Glu for Thr466 abolished this interaction and EFV, but did not impair the novel interaction responsible for EHF. Phosphorylation of KLC1 at Thr466 increased in aged brains, and JIP1 binding to kinesin-1 decreased, suggesting that APP transport is impaired by aging. We conclude that phosphorylation of KLC1 at Thr466 regulates the velocity of transport of APP by kinesin-1 by modulating its interaction with JIP1b.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Cytoplasm / metabolism
  • Kinesin / metabolism*
  • Mice
  • Microtubule-Associated Proteins / metabolism*
  • Neurons / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Domains
  • Protein Structural Elements
  • Protein Transport

Substances

  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Mapk8ip protein, mouse
  • Microtubule-Associated Proteins
  • kinesin light-chain proteins
  • Kinesin