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J. Biol. Chem., Vol. 282, Issue 32, 23036-23043, August 10, 2007

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Structurally Unique Yeast and Mammalian Serine-Arginine Protein Kinases Catalyze Evolutionarily Conserved Phosphorylation Reactions^*

Randall Lukasiewicz¹, Adolfo Velazquez-Dones, Nhat Huynh, Jonathan Hagopian, Xiang-Dong Fu^¶, Joseph Adams, and Gourisankar Ghosh²

From the Departments of Chemistry & Biochemistry, ^¶Cellular & Molecular Medicine, and Pharmacology, University of California, San Diego, La Jolla, California 92093-0375

The mammalian serine-arginine (SR) protein, ASF/SF2, contains multiple contiguous RS dipeptides at the C terminus, and 12 of these serines are processively phosphorylated by the SR protein kinase 1 (SRPK1). We have recently shown that a docking motif in ASF/SF2 specifically interacts with a groove in SRPK1, and this interaction is necessary for processive phosphorylation. We previously showed that SRPK1 and its yeast ortholog Sky1p maintain their active conformations using diverse structural strategies. Here we tested if the mechanism of ASF/SF2 phosphorylation by SRPK is evolutionarily conserved. We show that Sky1p forms a stable complex with its heterologous mammalian substrate ASF/SF2 and processively phosphorylates the same sites as SRPK1. We further show that Sky1p utilizes the same docking groove to bind yeast SR-like protein Gbp2p and phosphorylates all three serines present in a contiguous RS dipeptide stretch. However, the mechanism of Gbp2p phosphorylation appears to be non-processive. Thus, there are physical attributes of SR and SR-like substrates that dictate the mechanism of phosphorylation, whereas the ability to processively phosphorylate substrates is inherent to SR protein kinases.

Received for publication, December 11, 2006 , and in revised form, May 14, 2007.

^* This work was supported in part by the University of California and by National Institutes of Health (NIH) Grant GM67969. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by pre-doctoral training grants: the Molecular Biophysics Training Grant GM08326 (NIH) and the Growth Regulation & Oncogenesis Training Grant T32 CA009523 (NCI/NIH).

² To whom correspondence should be addressed: Dept. of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, 3103 Natural Sciences Bldg., La Jolla, CA 92093-0375. Tel.: 858-822-0469; Fax: 858-534-7042; E-mail: gghosh{at}ucsd.edu.

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