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Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF(cyclin F) complex

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journal contribution
posted on 2017-10-11, 00:00 authored by A Lee, S L Rayner, A De Luca, S S L Gwee, M Morsch, Vinod SundaramoorthyVinod Sundaramoorthy, H Shahheydari, A Ragagnin, B Shi, S Yang, K L Williams, E K Don, A K Walker, K Y Zhang, J J Yerbury, N J Cole, J D Atkin, I P Blair, M P Molloy, R S Chung

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that is characterized by progressive weakness, paralysis and muscle loss often resulting in patient death within 3–5 years of diagnosis. Recently, we identified disease-linked mutations in the
CCNF
gene, which encodes the cyclin F protein, in cohorts of patients with familial and sporadic ALS and frontotemporal dementia (FTD) (Williams KL
et al
. 2016
Nat. Commun.
7
, 11253. (
doi:10.1038/ncomms11253
)). Cyclin F is a part of a Skp1-Cul-F-box (SCF) E3 ubiquitin-protein ligase complex and is responsible for ubiquitylating proteins for degradation by the proteasome. In this study, we investigated the phosphorylation status of cyclin F and the effect of the serine to glycine substitution at site 621 (S621G) on E3 ligase activity. This specific mutation (S621G) was found in a multi-generational Australian family with ALS/FTD. We identified seven phosphorylation sites on cyclin F, of which five are newly reported including Ser621. These phosphorylation sites were mostly identified within the PEST (proline, glutamic acid, serine and threonine) sequence located at the C-terminus of cyclin F. Additionally, we determined that casein kinase II (CK2) can phosphorylate Ser621 and thereby regulate the E3 ligase activity of the SCF
(cyclin F)
complex. Furthermore, the S621G mutation in cyclin F prevents phosphorylation by CK2 and confers elevated Lys48-ubiquitylation activity, a hallmark of ALS/FTD pathology. These findings highlight the importance of phosphorylation in regulating the activity of the SCF
(cyclin F)
E3 ligase complex that can affect downstream processes and may lead to defective motor neuron development, neuron degeneration and ultimately ALS and FTD.

History

Journal

Open Biology

Volume

7

Issue

10

Article number

170058

Pagination

1 - 11

Publisher

Royal Society

Location

London, Eng.

ISSN

2046-2441

eISSN

2046-2441

Language

English

Publication classification

C1 Refereed article in a scholarly journal

Copyright notice

2017, The Author(s)