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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

Lee, A, Rayner, SL, De Luca, A, Gwee, SSL, Morsch, M, Sundaramoorthy, Vinod, Shahheydari, H, Ragagnin, A, Shi, B, Yang, S, Williams, KL, Don, EK, Walker, AK, Zhang, KY, Yerbury, JJ, Cole, NJ, Atkin, JD, Blair, IP, Molloy, MP and Chung, RS 2017, Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF(cyclin F) complex, Open Biology, vol. 7, no. 10, pp. 1-11, doi: 10.1098/rsob.170058.

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Title Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF(cyclin F) complex
Formatted title Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF(cyclin F) complex
Author(s) Lee, A
Rayner, SL
De Luca, A
Gwee, SSL
Morsch, M
Sundaramoorthy, VinodORCID iD for Sundaramoorthy, Vinod orcid.org/0000-0001-6309-8031
Shahheydari, H
Ragagnin, A
Shi, B
Yang, S
Williams, KL
Don, EK
Walker, AK
Zhang, KY
Yerbury, JJ
Cole, NJ
Atkin, JD
Blair, IP
Molloy, MP
Chung, RS
Journal name Open Biology
Volume number 7
Issue number 10
Article ID 170058
Start page 1
End page 11
Total pages 11
Publisher Royal Society
Place of publication London, Eng.
Publication date 2017-10-11
ISSN 2046-2441
2046-2441
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
ubiquitylation
phosphorylation
CCNF
cyclin F
amyotrophic lateral sclerosis
frontotemporal dementia
AMYOTROPHIC-LATERAL-SCLEROSIS
FRONTOTEMPORAL LOBAR DEGENERATION
HEXANUCLEOTIDE REPEAT
TDP-43 PROTEINOPATHY
BOX PROTEINS
MUTATIONS
ALS
REVEALS
C9ORF72
SITES
Summary 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.
Language eng
DOI 10.1098/rsob.170058
Indigenous content off
Field of Research 0601 Biochemistry and Cell Biology
0605 Microbiology
1107 Immunology
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2017, The Author(s)
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30136685

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.