Phosphorylation of FEZ1 by Microtubule Affinity Regulating Kinases regulates its function in presynaptic protein trafficking.

Journal Article (Journal Article)

Adapters bind motor proteins to cargoes and therefore play essential roles in Kinesin-1 mediated intracellular transport. The regulatory mechanisms governing adapter functions and the spectrum of cargoes recognized by individual adapters remain poorly defined. Here, we show that cargoes transported by the Kinesin-1 adapter FEZ1 are enriched for presynaptic components and identify that specific phosphorylation of FEZ1 at its serine 58 regulatory site is mediated by microtubule affinity-regulating kinases (MARK/PAR-1). Loss of MARK/PAR-1 impairs axonal transport, with adapter and cargo abnormally co-aggregating in neuronal cell bodies and axons. Presynaptic specializations are markedly reduced and distorted in FEZ1 and MARK/PAR-1 mutants. Strikingly, abnormal co-aggregates of unphosphorylated FEZ1, Kinesin-1 and its putative cargoes are present in brains of transgenic mice modelling aspects of Alzheimer's disease, a neurodegenerative disorder exhibiting impaired axonal transport and altered MARK activity. Our findings suggest that perturbed FEZ1-mediated synaptic delivery of proteins arising from abnormal signalling potentially contributes to the process of neurodegeneration.

Full Text

Duke Authors

Cited Authors

  • Butkevich, E; Härtig, W; Nikolov, M; Erck, C; Grosche, J; Urlaub, H; Schmidt, CF; Klopfenstein, DR; Chua, JJE

Published Date

  • June 2016

Published In

Volume / Issue

  • 6 /

Start / End Page

  • 26965 -

PubMed ID

  • 27247180

Pubmed Central ID

  • PMC4887895

Electronic International Standard Serial Number (EISSN)

  • 2045-2322

International Standard Serial Number (ISSN)

  • 2045-2322

Digital Object Identifier (DOI)

  • 10.1038/srep26965


  • eng