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Structural basis of Cdk7 activation by dual T-loop phosphorylation.

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Dual phosphorylation of Cyclin-dependent kinase 7 (Cdk7) regulates its function. The S164 phosphorylation aids complex formation, while T170 enhances activity towards transcription substrates like RNA polymerase II.

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Area of Science:

  • Molecular Biology
  • Biochemistry
  • Structural Biology

Background:

  • Cyclin-dependent kinase 7 (Cdk7) is crucial for cell-cycle progression and transcription.
  • Cdk7 functions as a CDK-activating kinase (CAK) and is part of transcription factor TFIIH.
  • Cdk7 activity is modulated by phosphorylation at T170 and S164 within its activation segment.

Purpose of the Study:

  • To elucidate the structural and functional roles of dual T-loop phosphorylations in the human Cdk7/Cyclin H/Mat1 complex.
  • To investigate how individual and combined phosphorylations affect Cdk7's kinase activity and substrate specificity.

Main Methods:

  • Determined the crystal structure of the human Cdk7/Cyclin H/Mat1 complex with both T170 and S164 phosphorylations.
  • Assessed kinase activity and substrate recognition dependent on individual and dual T-loop phosphorylations.
  • Investigated the phosphorylation order of S164 and T170 in human cells.

Main Results:

  • The crystal structure reveals pT170 coordinating conserved residues, while pS164 forms a unique arginine network within the ternary complex.
  • CAK activity is independent of T-loop phosphorylation, but pT170 significantly enhances activity towards non-CDK substrates.
  • Dual phosphorylation stimulates multisite phosphorylation of RNA polymerase II CTD and SPT5 CTR.

Conclusions:

  • Cdk7 activation in human cells is a sequential process: S164 phosphorylation precedes and potentially primes T170 phosphorylation.
  • pS164 supports tripartite complex formation and may influence processivity.
  • pT170 enhances Cdk7's activity towards critical transcriptional substrates, highlighting dual phosphorylation's regulatory role.