PXD004531

PXD004531 is an original dataset announced via ProteomeXchange.

Title	Phosphorylation of Cyclin F at Serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF(Cyclin F) complex.
Description	Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder that is characterized by progressive weakness, paralysis and cachexia often resulting in patient death within 3-5 years of diagnosis. Recently, we identified mutations to the CCNF gene, which encodes the Cyclin F protein, in cohorts of patients with familial and sporadic ALS (1). Cyclin F is a part of a Skp1-Cul-F-box (SCF) E3 ubiquitin-protein ligase complex and is responsible for ubiquitinating proteins for the degradation by the proteasome. In this study, we investigated the phosphorylation status of Cyclin F and the effect of the serine mutation at site 621 to glycine on E3 ligase Lys48-specific ubiquitylation activity. We identified seven phosphorylation sites on Cyclin F, of which five were unique including Ser621. These phosphorylation sites were mostly identified within the PEST sequence of Cyclin F at the C-terminus. Additionally, we determined that Casein Kinase II (CK2) was responsible for phosphorylating Ser621 and controls the E3 ligase activity of the SCF(Cyclin F) complex. Thus, the glycine mutation at this site on Cyclin F prevents phosphorylation by CK2 and confers elevated Lys48-ubiquitylation activity, a hallmark of ALS pathogenesis. These findings highlight the convergence of post-translational modifications (ubiquitylation and phosphorylation) to sustain cellular homeostasis, and aberrations such as a single missense mutation can affect downstream cellular processes and lead to aberrant motor neuron development, neuron degeneration and ultimately ALS.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:30:53.295.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Albert Lee
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2016-07-08 03:19:51	ID requested
1	2017-12-08 03:49:55	announced
⏵ 2	2024-10-22 04:30:54	announced	2024-10-22: Updated project metadata.

10.1098/rsob.170058;

Lee A, Rayner SL, De Luca A, Gwee SSL, Morsch M, Sundaramoorthy V, 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, complex. Open Biol, 7(10):(2017) [pubmed]

curator keyword: Biological

submitter keyword: ALS, phosphorylation,ubiquitylation, E3 ligase

Albert Lee
contact affiliation	Department of Biomedical Sciences, Macquarie University, North Ryde, NSW, 2109, Australia
contact email	albert.lee@mq.edu.au
lab head
Albert Lee
contact affiliation	Macquarie University
contact email	albert.lee@mq.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD004531
     1. Label: PRIDE project
     2. Name: Phosphorylation of Cyclin F at Serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF(Cyclin F) complex.