UC San Diego

Protein phosphorylation and dephosphorylation plays a critical role in the regulation of many important cellular processes. The protein families responsible for this, the kinases and phosphatases, have been the focus of enormous amounts of research. However, our knowledge of these families is in many respects still incomplete, as prior studies have oftentimes focused only on humans and other higher eukaryotes. The advent of the genome sequencing era now allows us to examine these protein families on a more global scale. I present here a study of protein kinase and phosphatase families in 115 completely sequenced genomes. This is an important contribution towards understanding not only which families are present in different lineages, but also how the evolution of these families relates to each other. In chapter 2, I define the human kinome using a method called iGAP. This method combines sequence similarity and fold recognition methods to annotate proteins. I searched the human proteome for members of the eukaryotic protein kinase-like superfamily and identified two novel putative kinases. In subsequent chapters, I extend this focus to include phosphatases and other genomes in the Eukarya, Bacteria and Archaea superkingdoms. Chapter 3 is centered on phosphatases. I built profile hidden Markov models of known phosphatase families and searched 115 complete proteomes for the presence or absence of these families. I define which genomes and lineages contain particular families and discuss what we can learn about the evolution of the phosphatase families. In chapter 4, I present a similar study of the kinases. I built models for microbial and eukaryotic kinase families and searched the same 115 proteomes for the presence or absence of the kinase families. I report here the results and discuss the evolutionary implications, incorporating past sequence and structure-based research of the evolution of the protein kinase-like superfamily. Chapter 5 compares and contrasts the evolutionary patterns of protein kinase and phosphatase families that target either the same substrate or each other. I report the presence or absence of these families in the aforementioned species. I then compare the phylogenetic profiles of these families and discuss how the evolution of each family relates to the other