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¶ and
*Yale University School of Medicine, Department of Molecular
Biophysics and Biochemistry, New Haven, Connecticut 06520-8024;
Cell cycle progression is controlled by the sequential functions of
cyclin-dependent kinases (cdks). Cdk activation requires phosphorylation of a key residue (on sites equivalent to Thr-160 in
human cdk2) carried out by the cdk-activating kinase (CAK). Human CAK
has been identified as a p40MO15/cyclin H/MAT1 complex that
also functions as part of transcription factor IIH (TFIIH) where it
phosphorylates multiple transcriptional components including the
C-terminal domain (CTD) of the large subunit of RNA polymerase
II. In contrast, CAK from budding yeast consists of a single
polypeptide (Cak1p), is not a component of TFIIH, and lacks CTD kinase
activity. Here we report that Cak1p and p40MO15 have
strikingly different substrate specificities. Cak1p preferentially phosphorylated monomeric cdks, whereas p40MO15
preferentially phosphorylated cdk/cyclin complexes. Furthermore, p40MO15 only phosphorylated cdk6 bound to cyclin D3,
whereas Cak1p recognized monomeric cdk6 and cdk6 bound to cyclin D1,
D2, or D3. We also found that cdk inhibitors, including
p21CIP1, p27KIP1, p57KIP2,
p16INK4a, and p18INK4c, could block
phosphorylation by p40MO15 but not phosphorylation by
Cak1p. Our results demonstrate that although both Cak1p and
p40MO15 activate cdks by phosphorylating the same residue,
the structural mechanisms underlying the enzyme-substrate recognition
differ greatly. Structural and physiological implications of these
findings will be discussed.
Cellular Biochemistry and Biophysics Program,
¶Howard Hughes Medical Institute, Memorial Sloan-Kettering
Cancer Center, New York, New York 10021; and
Massachusetts General Hospital Cancer Center, Laboratory
of Molecular Oncology, Charlestown, Massachusetts 02129
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