Eukaryotic protein kinases transfer a phosphate from a nucleoside triphosphate to a protein substrate. The eukaryotic protein kinases are homologous and therefore exhibit significant structural similarity but can be divided into eight subfamilies with closer structural and functional relationships. The CK1 subfamily is ubiquitous and highly conserved within Eukarya, and has members that are relevant to regulating cell proliferation and differentiation, chromosomal segregation, and circadian rhythm. In humans, CK1s have been linked to neurodegenerative diseases and cancer. We are investigating regulation of CK1 activity by phosphorylation, using yeast CK1 protein kinases as models. We have previously identified phosphorylation sites that negatively regulate activity through in vitro and in vivo studies of phosphorylation-mimicking and �preventing mutations. In this study, we have used NAMD to investigate the effect of mutations on protein structure in silico. We have identified structural changes large enough to modify kinase activity, for example S179 shifts towards a positively charged RD pocket by 3-4 � upon phosphorylation or mutation to a glutamic acid. The phosphorylated amino acid is also subject to a much more restrictive potential of mean force over the coordinate between S179 and the RD pocket. The simulation results will be further contextualized in terms of the laboratory work.

Molecular modeling of casein kinase-1 to determine relevance of conserved potential phosphorylation sites

245th National Meeting (2013)

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