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  Phosphorylation of FEZ1 by microtubule affinity regulating kinases regulates its function in presynaptic protein trafficking.

Butkevich, E., Hartig, W., Nikolov, M., Erck, C., Grosche, J., Urlaub, H., et al. (2016). Phosphorylation of FEZ1 by microtubule affinity regulating kinases regulates its function in presynaptic protein trafficking. Scientific Reports, 6: 26965. doi:10.1038/srep26965.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-E494-D Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-9E72-E
Genre: Journal Article

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 Creators:
Butkevich, E., Author
Hartig, W., Author
Nikolov, M.1, Author              
Erck, C., Author
Grosche, J., Author
Urlaub, H.1, Author              
Schmidt, C. F., Author
Klopfenstein, D. R., Author
Chua, J. J. E.2, Author              
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              
2Research Group of Protein Trafficking in Synaptic Development and Function, MPI for Biophysical Chemistry, Max Planck Society, ou_1933287              

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 Abstract: 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.

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Language(s): eng - English
 Dates: 2016-06-01
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1038/srep26965
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Title: Scientific Reports
Source Genre: Journal
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Pages: 15 Volume / Issue: 6 Sequence Number: 26965 Start / End Page: - Identifier: -