Phosphoregulation of a novel cyclin (CCNF) associated with Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common and convergent molecular and pathogenic features. Prof Ian Blair and colleagues from Macquarie University recently discovered a gene, CCNF that is mutated in some familiar cases of ALS. Further detailed investigation using APAF mass spectrometry techniques and equipment enabled Dr Albert Lee and colleagues to characterise five new phosphorylation sites on CCNF, including Ser621 which is a site of mutation (S621G). It was shown that casein kinase II (CK2) can phosphorylate Ser621 and thereby regulate the E3 ligase activity of the SCF(cyclin F) complex.

The convergence of phosphorylation and disease-linked mutation of a single residue (S621G) indicates that this site is of particular importance for ALS/FTD. Our findings suggest that precisely regulated phosphorylation of Ser621 in cyclin F is crucial for the maintenance of appropriate activity of ubiquitylation-dependent protein degradative pathways.

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. Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF((cyclin F)) complex. Open Biol . 2017 Oct;7(10). pii:170058. doi: 10.1098/rsob.170058.