Cyclin Dependent Kinase

An introduction
Protein Kinase
Change the activity of target protein by
adding phosphate group.
Types of kinases
Serine/Threonine – specific kinase.
Tyrosine – specific kinase.
Histidine – specific kinase.
Cyclin Dependent Kinase
A member of Serine/threonine – specific
kinase family.
Activated by regulatory sub-unit known
as CYCLIN.
20 Cdks and 25 Cyclins are identified by
HUMAN SEQUENCING.
Still function of every cdks Not Fully
Identified.
Types of CDKs
CDK 1; Cyclin A, Cyclin B
CDK 2; Cyclin A, Cyclin E
CDK 3; Cyclin C ?
CDK 4; Cyclin D(1-3)
CDK 5; p35,p39
CDK 6; Cyclin D(1-3)
CDK 7; Cyclin H
CDK 8; Cyclin C
CDK 9; Cyclin T(1,2a,2b),Cyclin K
CDK 10;
CDK 11; Cyclin L
CDK 12; Cyclin L
CDK 13; Cyclin L
Phylogenetic Analysis of CDKs

Ref 1
Cdk Structure
PSTAIRE helix: alpha helix in the amino-terminal lobe of Cdks
(also known as the alpha helix), which interacts with cyclin and is moved
inward upon cyclin binding, resulting in reorientation of key active-site
residues. The name of this helix comes from its amino-acid sequence, which is
conserved among all major Cdks.
T-loop: flexible loop adjacent to the active site of Cdks, named for the
threonine whose phosphorylation is required for maximal activity. Sometimes called
the activation loop.
L12 helix: small alpha helix adjacent to the T-loop in the active site of Cdk2
(residues 147–151), which changes structure to a beta strand upon cyclin binding
Ref 2
Cdk2 with Cyclin A Ref 3

activation
segments
PSTAIRE
helix

Ref 4
Ref 5
CDK 7

Ref 6

CDK7
CDK9 with cyclin T1 and TAT Protein

Ref 7
 ATP
Cyclin

Cdk9 Tat p
 ATP

Ribbon diagram of the human

CDK10 (a) without ATP and (b) in complex
with ATP
Ref 8
FUNCTION OF CDKS
CellCycle Regulation
Transcription
Neuronal Function
Cellular Differentiation
Apoptosis
Cell cycle Regulation
Transcription
Cdks phosphorylate serine 5 residue of
RNA pol II at CTD (carboxyl terminal
domain)
Cdk7/cyclin H is the part of the
transcription factor II H (TF II H)
Cdk9/cyclin T forms the positive
transcription elongation factor-b (P-TEFb)
This complex add phosphorus at serine 2
residue of RNA pol II
Transcription contd….
Cdk8/cyclin C complex work as
transcription repressor
Cdk11/cyclin L also shows dual role in
transcription
Neuronal Function
Cdk5 has an essential role in the central and
peripheral nervous system
Cdk5 regulates the cyto-architecture of the
developing brain and neuronal migration in mitotic
neurons
It also shows important function in
◦ Cytoskeleton dynamics
◦ Synaptic plasticity
◦ Drug addiction
◦ Synaptic endocytosis
◦ Neurotransmitter release
Cellular differentiation
Cdk5 act as positive modulator of early
myogenesis
Cdk9 induces the differentiation in tissues
The degree of Cdk9 directly correlates
with the degree of differentiation of
primary neuroectodermal and
neuroblastoma tumor cells
Apoptosis
Cdk2 and Cdk5 have been shows
different roles in induction and
suppression of apoptosis in different
tissues
REGULATION OF CDKS
Transcription & translation of their
subunit.
On the formation of CDK\CYCLIN
complex.
By post translation modification
◦ Phosphorylation by Wee 1 & Myt 1 enzyme at
thr 14 & thy 15 residue.
◦ Phosphorylation by CAK at thr 160 residue.
REGULATION OF CDKS
By NATURAL INHIBITOR like
◦ Cip/Kip inhibitor –p21,p27,p57
◦ INK4 inhibitor – p15,p16,p18 and
p19.
SYNTHETIC INHIBITOR OF CDKS
Broad Cdk inhibitors : Flavopiridol
Specific Cdk inhibitors : Roscovitine
Multiple Target inhibitors :
compound targeting Cdks as well as
additional kinases such as VEGFR or
PDGER.
ROLE OF CDKS IN
DISEASE
Malaria
Several Cdks have been characterized
from the genome of Malaria-causing
protozoan Plasmodium falciparum
Pfmrk is homologs to human Cdk7 and
acting as CAK(cdk activator kinase) in
malarial parasite cell cycle.
So it is most suitable target of the drug
resistance parasite
Cancer
Failure of Cdks regulation leads high rate
of its activity which may be caused the
high cell proliferation and fail of cell
cycle regulation
Due to this cell escape from different
check point like G1 & G2
This leads the cell became cancerous
Cancer contd…….

Tumor
like breast
Hyper , colon
Over activatio and
expressi n of prostate
on of Cdk1
cyclin
B1
Cancer countd………

Ovarian
carcinoma
Deregulation of Lung carcinoma
Cdk2
Over
expression of
Inactivation of cyclin E and/or
Cip/kip protein cyclin A
Neurological Disorders
Deregulation of cdk5 may be involved in
the pathogenesis of several
neurodegenerative disorders like :
◦ Alzheimer`s disease
◦ Parkinson`s disease
◦ Traumatic brain injury
Other diseases
Type 2 Diabetes
◦ Cdk5 prevent insulin secretion by pancreatic
cells and its inhibition glucose-dependent
secretion
Viral infection
◦ Cellular cdks are also involved in replication
of some viruses(CMV,HPV,HIV) use cellular
cdks (cdk2,cdk9) for their transcription.
Cyclin Dependent kinase
Inhibitors in clinical trails
References
1. Malumbres M. and M.Barbacid, “Mammalian Cyclin-dependent kinases”.
Trends Biochem Sci,2005.30(11):P.630-41 .
2. Book “The Cell-Cycle Control System” Chapter 3, New Science Press
Ltd 2007 p(31-32)
3. De Bondt, H.L. et al.: Crystal structure of cyclin dependent kinase 2.
Nature 1993, 363:595–602..
4. Philip J. Daya et al.: Crystal structure of human CDK4 in complex with
a D-type cyclin. PNAS March 17, 2009 vol. 106:p(4166–4170).
5. Mapelli M. “ The Structural Perspective on CDK5”the Nero sci.
6. Lolli G. “The Crystal Structure of Human CDK7 and Its Protein
Recognition Properties” Structure, Vol. 12, 2067–2079, November, 2004
7. Tahir H. Tahirov “Crystal structure of HIV-1 Tat complexed with
human P-TEFb”. Vol 46510 June 2010doi:10.1038/nature09131
8. Molscript (Kraulis,1991) and Raster3D (Merritt et al., 1997).