Structural Analysis of Domain Swapping in the Protein Kinase: Crystal Structure of Human Ste20 OSR1 Kinase Domain

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2007-12-18

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Lee, Seung-Jae

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Abstract

Ste20p (Sterile 20 protein) is a yeast MAP4K involved in the pheromoneresponsive MAPK cascade of the mating pathway. Recent studies reveal that its homologs in mammals, Drosophila melanogaster, Caenorhabditis elegans and other organisms constitute a large emerging group of protein kinases including 28 members in human. The Ste20p family has gained remarkable interest, due to the recent finding that it has various intracellular regulatory effects including the regulation of apoptosis and rearrangement of the cytoskeleton triggering cell-shape changes and cell motility. Moreover, from the viewpoint of structural biology, it is intriguing that the Ste20p family is characterized by the presence of a conserved kinase domain and a noncatalytic region of great diversity at various locations. Despite recent structural studies of Ste20p kinases such as PAK1 or TAO2, the mechanism of kinase regualtion in this family still remains to be investigated. Thus, in order to deepen our understanding of Ste20p from a structural viewpoint, the OSR1 kinase, which belongs to the GCK VI subfamily, was crystallized. In this dissertation, I present the crystal structure of the OSR1 kinase domain in an inactive conformation. This crystallographic result demonstrates the unexpected finding that the OSR1 kinase domain is dimerized in domain-swapped manner, which is a novel mode of protein-protein interaction in the protein kinase family. The detailed structural analysis shows that alpha EF helix and the P+1 loop region located in the activation segment were completely swapped between two monomers. The DFG magnesium binding loop and the N-terminal F-helix seem to function as anchors for the hinge loop, based upon the structural alignment with other domain-swapped Ste20p kinases, which were reported after I completed the OSR1 structure determination. Several Ste20p kinases also form domain-swapped dimers in a strikingly similar manner to OSR1.

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