Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution.
To explore the mechanisms and evolution of cell-cycle control, we analyzed the position and conservation of large numbers of phosphorylation sites for the cyclin-dependent kinase Cdk1 in the budding yeast Saccharomyces cerevisiae. We combined specific chemical inhibition of Cdk1 with quantitative mass spectrometry to identify the positions of 547 phosphorylation sites on 308 Cdk1 substrates in vivo. Comparisons of these substrates with orthologs throughout the ascomycete lineage revealed that the position of most phosphorylation sites is not conserved in evolution; instead, clusters of sites shift position in rapidly evolving disordered regions. We propose that the regulation of protein function by phosphorylation often depends on simple nonspecific mechanisms that disrupt or enhance protein-protein interactions. The gain or loss of phosphorylation sites in rapidly evolving regions could facilitate the evolution of kinase-signaling circuits.
Holt
Liam J
LJ
Departments of Physiology and Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Tuch
Brian B
BB
Villén
Judit
J
Johnson
Alexander D
AD
Gygi
Steven P
SP
Morgan
David O
DO
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001203:Ascomycota / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005075:Biological Evolution; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002453:Cell Cycle; D002468:Cell Physiological Phenomena; D019295:Computational Biology; D019143:Evolution, Molecular; D008969:Molecular Sequence Data; D010748:Phosphopeptides / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D010802:Phylogeny; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013379:Substrate Specificity
D010748:Phosphopeptides; D029701:Saccharomyces cerevisiae Proteins; D016203:CDC2 Protein Kinase