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Human and yeast Cdk-activating kinases (CAKs) display distinct substrate specificities

Kaldis, Philipp LU orcid ; Russo, Alicia A. ; Chou, Hubert S. ; Pavletich, Nikola P. and Solomon, Mark J. (1998) In Molecular Biology of the Cell 9(9). p.2545-2560
Abstract

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 p40(MO15)/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 p40(MO15) have strikingly different substrate... (More)

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 p40(MO15)/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 p40(MO15) have strikingly different substrate specificities. Cak1p preferentially phosphorylated monomeric cdks, whereas p40(MO15) preferentially phosphorylated cdk/cyclin complexes. Furthermore, p40(MO15) 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 p21(CIP1), p27(KIP1), p57(KIP2), p16(INK4a), and p18(INK4c), could block phosphorylation by p40(MO15) but not phosphorylation by Cak1p. Our results demonstrate that although both Cak1p and p40(MO15) 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.

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author
; ; ; and
publishing date
type
Contribution to journal
publication status
published
in
Molecular Biology of the Cell
volume
9
issue
9
pages
2545 - 2560
publisher
American Society for Cell Biology
external identifiers
  • pmid:9725911
  • scopus:0031686960
ISSN
1059-1524
DOI
10.1091/mbc.9.9.2545
language
English
LU publication?
no
id
dea9256b-86e2-45b5-8296-e2e1bb95492d
date added to LUP
2019-09-18 14:35:36
date last changed
2024-04-02 18:41:42
@article{dea9256b-86e2-45b5-8296-e2e1bb95492d,
  abstract     = {{<p>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 p40(MO15)/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 p40(MO15) have strikingly different substrate specificities. Cak1p preferentially phosphorylated monomeric cdks, whereas p40(MO15) preferentially phosphorylated cdk/cyclin complexes. Furthermore, p40(MO15) 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 p21(CIP1), p27(KIP1), p57(KIP2), p16(INK4a), and p18(INK4c), could block phosphorylation by p40(MO15) but not phosphorylation by Cak1p. Our results demonstrate that although both Cak1p and p40(MO15) 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.</p>}},
  author       = {{Kaldis, Philipp and Russo, Alicia A. and Chou, Hubert S. and Pavletich, Nikola P. and Solomon, Mark J.}},
  issn         = {{1059-1524}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{9}},
  pages        = {{2545--2560}},
  publisher    = {{American Society for Cell Biology}},
  series       = {{Molecular Biology of the Cell}},
  title        = {{Human and yeast Cdk-activating kinases (CAKs) display distinct substrate specificities}},
  url          = {{http://dx.doi.org/10.1091/mbc.9.9.2545}},
  doi          = {{10.1091/mbc.9.9.2545}},
  volume       = {{9}},
  year         = {{1998}},
}