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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
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 cycl...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666078/ https://www.ncbi.nlm.nih.gov/pubmed/29021214 http://dx.doi.org/10.1098/rsob.170058 |
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author | Lee, Albert Rayner, Stephanie L. De Luca, Alana Gwee, Serene S. L. Morsch, Marco Sundaramoorthy, Vinod Shahheydari, Hamideh Ragagnin, Audrey Shi, Bingyang Yang, Shu Williams, Kelly L. Don, Emily K. Walker, Adam K. Zhang, Katharine Y. Yerbury, Justin J. Cole, Nicholas J. Atkin, Julie D. Blair, Ian P. Molloy, Mark P. Chung, Roger S. |
author_facet | Lee, Albert Rayner, Stephanie L. De Luca, Alana Gwee, Serene S. L. Morsch, Marco Sundaramoorthy, Vinod Shahheydari, Hamideh Ragagnin, Audrey Shi, Bingyang Yang, Shu Williams, Kelly L. Don, Emily K. Walker, Adam K. Zhang, Katharine Y. Yerbury, Justin J. Cole, Nicholas J. Atkin, Julie D. Blair, Ian P. Molloy, Mark P. Chung, Roger S. |
author_sort | Lee, Albert |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5666078 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The Royal Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-56660782017-11-15 Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF((cyclin F)) complex Lee, Albert Rayner, Stephanie L. De Luca, Alana Gwee, Serene S. L. Morsch, Marco Sundaramoorthy, Vinod Shahheydari, Hamideh Ragagnin, Audrey Shi, Bingyang Yang, Shu Williams, Kelly L. Don, Emily K. Walker, Adam K. Zhang, Katharine Y. Yerbury, Justin J. Cole, Nicholas J. Atkin, Julie D. Blair, Ian P. Molloy, Mark P. Chung, Roger S. Open Biol Research 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. The Royal Society 2017-10-11 /pmc/articles/PMC5666078/ /pubmed/29021214 http://dx.doi.org/10.1098/rsob.170058 Text en © 2017 The Authors. http://creativecommons.org/licenses/by/4.0/ Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. |
spellingShingle | Research Lee, Albert Rayner, Stephanie L. De Luca, Alana Gwee, Serene S. L. Morsch, Marco Sundaramoorthy, Vinod Shahheydari, Hamideh Ragagnin, Audrey Shi, Bingyang Yang, Shu Williams, Kelly L. Don, Emily K. Walker, Adam K. Zhang, Katharine Y. Yerbury, Justin J. Cole, Nicholas J. Atkin, Julie D. Blair, Ian P. Molloy, Mark P. Chung, Roger S. Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF((cyclin F)) complex |
title | Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF((cyclin F)) complex |
title_full | Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF((cyclin F)) complex |
title_fullStr | Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF((cyclin F)) complex |
title_full_unstemmed | Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF((cyclin F)) complex |
title_short | Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF((cyclin F)) complex |
title_sort | casein kinase ii phosphorylation of cyclin f at serine 621 regulates the lys48-ubiquitylation e3 ligase activity of the scf((cyclin f)) complex |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666078/ https://www.ncbi.nlm.nih.gov/pubmed/29021214 http://dx.doi.org/10.1098/rsob.170058 |
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