Proteomics

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Phosphorylation of Cyclin F at Serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF(Cyclin F) complex.


ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap Velos, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Kidney Cell

DISEASE(S): Amyotrophic Lateral Sclerosis

SUBMITTER: Albert Lee  

LAB HEAD: Albert Lee

PROVIDER: PXD004531 | Pride | 2017-12-08

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
140725_mCherryWT_IP_1906.raw Raw
140725_mCherryWT_MG_IP_1906.mgf Mgf
140725_mCherryWT_MG_IP_1906.msf Msf
140912_mCherryIP_WT.mgf Mgf
140912_mCherryIP_WT.msf Msf
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Publications


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 <i>CCNF</i> gene, which encodes the cyclin F protein, in cohorts of patients with familial and sporadic ALS and frontotemporal dementia (FTD) (Williams KL <i>et al</i> 2016 <i>Nat. Commun.</i><b>7</b>, 11253. (doi:10.1038/ncomms11253  ...[more]

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