sundaramoorthy-caseinkinase-2017.pdf (1.04 MB)
Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF(cyclin F) complex
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 ChungAmyotrophic 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 BiologyVolume
7Issue
10Article number
170058Pagination
1 - 11Publisher
Royal SocietyLocation
London, Eng.Publisher DOI
Link to full text
ISSN
2046-2441eISSN
2046-2441Language
EnglishPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2017, The Author(s)Usage metrics
Keywords
Science & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyubiquitylationphosphorylationCCNFcyclin Famyotrophic lateral sclerosisfrontotemporal dementiaAMYOTROPHIC-LATERAL-SCLEROSISFRONTOTEMPORAL LOBAR DEGENERATIONHEXANUCLEOTIDE REPEATTDP-43 PROTEINOPATHYBOX PROTEINSMUTATIONSALSREVEALSC9ORF72SITESMicrobiologyImmunology
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