The Cell Cycle: Principles of Control David Morgan
The Cell Cycle: Principles of Control David Morgan
The Cell Cycle: Principles of Control David Morgan
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<strong>Cell</strong> <strong>Cycle</strong> <strong>Control</strong> is based on CDKsCDKs are Activated at Specific StagesCDK Activity is Regulated by Cyclins3 Major Checkpoints:Start (G1/S and S-Phase Cyclins)Entry into Mitosis (M-Phase Cyclins)Metaphase-Anaphase (Anaphase Promoting Complex, APC)
DICgRNA-ASH1Kerry BloomMTs-GFPGrallert et al, G&D 2006
HisAv-mRFP1 (red) and EGFP-cid (green)Schuh et al., Current Biology, 2007Centrioles Microtubules Chromosomes
Levels <strong>of</strong> 3 Major Cyclins Oscillate During the <strong>Cell</strong> <strong>Cycle</strong>Basis for Oscillation <strong>of</strong> CDK-Cyclin Complexes Activity that Drive <strong>Cell</strong> <strong>Cycle</strong> EventsCDK levels are Constant and in Excess <strong>of</strong> Cyclins<strong>The</strong> APC Degrades Cyclins Turning Off CDKs
PSTAIRE HelixPSTAIRE Helix: Interacts With Cyclins and Moves Inwards Upon Binding. Alters Conformationto Better Bind and Hydrolyze ATP<strong>The</strong> Small L12 Helix Just Before the T-Loop Changes to beta-Strand Upon Cyclin Binding
Destruction BoxCyclin Fold:Two Compact Domain <strong>of</strong> 5 Alpha Helices EachCyclins Have a Conserved Helical CoreHomology Primarily in the Cyclin Box A1-A5MRAIL Sequence is an Hydrophobic Patch Contributing to Binding Certain SubstratesActivation SiteTwo Steps in CDK Activation:1- Cyclin Binding Alone is NOT Sufficient for Full Activity2- Full Activation Requires Phosphorylation by Cyclin Activation Kinases (CAKs)However, cyclin binding is the rate limiting stepCAK Activity always at high levelNot a <strong>Cell</strong> <strong>Cycle</strong> Regulated EventRole in Transcription (Basal Gene Transcription, Associates with TFIIH <strong>of</strong> RNA Pol II)
Monomer in Budding YeastFission Yeast: Between Budding Yeast and VertebratesVertebrates and Drosophila:Trimer with Cyclin H and MAT1Function <strong>of</strong> CAKs in Different SpeciesTrimeric CAKCDK ActivationTranscriptionMcs6: CDK ActivationMsc6: Transcription RegulationCsk1: CDK ActivationKin28 Only regulates TranscriptionCak1 Activates CDKs
Inhibitory Phosphorylation IS Highly ImportantTyr15 in all Major CDKsIn Animal <strong>Cell</strong>s: Also Adjacent Thr14 Blocks ActivityTyr15/Thr14 Located Near ATP-binding SiteBalance Phosphorylation -Dephosphorylation3 Members in Vertebrates!
Switch-like ActivationFully Active cyclin-CDK Complexes can be Inhibited by PhosphorylationOne / Two Inhibitory SitesWee1: Tyr15Myt1 Tyr15 and Thr14Dephosphorylation by CDC25 leads to reactivation
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