Sandbox 210
From Proteopedia
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[[Image:1h4l.jpg|left|200px]] | [[Image:1h4l.jpg|left|200px]] | ||
{{STRUCTURE_1h4l| PDB=1h4l | SCENE= }} | {{STRUCTURE_1h4l| PDB=1h4l | SCENE= }} | ||
| - | CDK means Cyclin Dependent Kinase. The cyclin-dependent kinases (CDKs) are a large family of serine–threonine kinases which control the eukaryotic cell cycle, when they are activated by the cyclin regulatory subunit. These kinases phosphorylate a very large number of protein in order to inactivate or activate them.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref> | ||
| - | + | == CDK5 – Cyclin dependent Kinase 5 == | |
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| + | CDK5 is a member of the '''cyclin dependent kinases protein family'''. Cyclin dependent kinases, a large family of serine–threonine kinases, play a crucial role in the regulation of the eukaryotic cell cycle. Since CDK5 plays only little role in cell cycle regulation processes, it is an unusual member of this protein family. It is rather involved in cell-cell communication, cell morphology and motility, and is indispensable for a correct neural development.<ref name="un">DOI 10.1007/s10571-007-9242-1</ref> | ||
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| + | CDK5 was identified as member of the CDK-family because of its 58 % sequence homology with mouse CDK1 and its 61 % sequence homology with human CDK2.<ref>PMCID: PMC50443</ref> | ||
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| + | Whereas CDKs are activated upon association with specific cyclins, the kinase activity of CDK5 is activated by its association with non-cyclin molecules such as p25, p35 or p39.[3, 4] | ||
| + | |||
| + | <ref name="premier">doi:10.1007/s00894-009-0629-4</ref> | ||
| - | CDK5 could form a complex with p25, an other protein. | ||
==Discovery of CDK5== | ==Discovery of CDK5== | ||
| - | Reported by four independent groups of scientists in 1992, Cdk5 had multiple names. A first group reported it as a neuronal Cdc2 like kinase (NCLK) characterized and cloned from rat brain c-DNA library as a Cdk that phosphorylates the lysine–serine–proline motif of neurofilaments. It was reported to have 58% amino acid sequence homology with mouse Cdk1 and 61% homology with human Cdk2. While looking for several Cdks, which play an important role in eukaryotic cell cycle, a second group found Cdk5/PSSALARE kinase (with an alpha C helix) among several other Cdks. A third group of scientists called the same molecule as brain proline-directed protein kinase (BPDK), reporting it in bovine brain with functional similarity to cdc2. In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules. Later in 1993, the nomenclature settled down to Cdk5 after identifying the 30 kDa protein subunit of the active enzyme.<ref name=" | + | Reported by four independent groups of scientists in 1992, Cdk5 had multiple names. A first group reported it as a neuronal Cdc2 like kinase (NCLK) characterized and cloned from rat brain c-DNA library as a Cdk that phosphorylates the lysine–serine–proline motif of neurofilaments. It was reported to have 58% amino acid sequence homology with mouse Cdk1 and 61% homology with human Cdk2. While looking for several Cdks, which play an important role in eukaryotic cell cycle, a second group found Cdk5/PSSALARE kinase (with an alpha C helix) among several other Cdks. A third group of scientists called the same molecule as brain proline-directed protein kinase (BPDK), reporting it in bovine brain with functional similarity to cdc2. In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules. Later in 1993, the nomenclature settled down to Cdk5 after identifying the 30 kDa protein subunit of the active enzyme.<ref name="un" /> |
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The neurotoxic activator p25 activates CDK5 in one step by tethering the T-loop in the extended conformation and exposing CDK5's active site for kinase activity. When activated by p25, CDK5 causes the death of neurons, leading to neurodegenerative diseases. | The neurotoxic activator p25 activates CDK5 in one step by tethering the T-loop in the extended conformation and exposing CDK5's active site for kinase activity. When activated by p25, CDK5 causes the death of neurons, leading to neurodegenerative diseases. | ||
Deregulation of CDK5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases. | Deregulation of CDK5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases. | ||
| - | Sometimes, p35, the activator of CDK5, is cleaved in p25 by a protease calcium-dependent, the calpain. This cut form of p35 (p25) is able to activate CDK5 and to trigger a modification of its cellular localization. It can increase its activity too. In Alzheimer’s disease or in the amyotrophic lateral sclerosis, when the ratio of p25 over p35 increases, it creates an hyperactivity of CDK5 which could hyperphosphorylate the protein Tau.<ref name=" | + | Sometimes, p35, the activator of CDK5, is cleaved in p25 by a protease calcium-dependent, the calpain. This cut form of p35 (p25) is able to activate CDK5 and to trigger a modification of its cellular localization. It can increase its activity too. In Alzheimer’s disease or in the amyotrophic lateral sclerosis, when the ratio of p25 over p35 increases, it creates an hyperactivity of CDK5 which could hyperphosphorylate the protein Tau.<ref name="un" /> |
==References== | ==References== | ||
Revision as of 15:26, 30 December 2011
Contents |
CDK5-p25 complex
CDK5 – Cyclin dependent Kinase 5
CDK5 is a member of the cyclin dependent kinases protein family. Cyclin dependent kinases, a large family of serine–threonine kinases, play a crucial role in the regulation of the eukaryotic cell cycle. Since CDK5 plays only little role in cell cycle regulation processes, it is an unusual member of this protein family. It is rather involved in cell-cell communication, cell morphology and motility, and is indispensable for a correct neural development.[1]
CDK5 was identified as member of the CDK-family because of its 58 % sequence homology with mouse CDK1 and its 61 % sequence homology with human CDK2.[2]
Whereas CDKs are activated upon association with specific cyclins, the kinase activity of CDK5 is activated by its association with non-cyclin molecules such as p25, p35 or p39.[3, 4]
Discovery of CDK5
Reported by four independent groups of scientists in 1992, Cdk5 had multiple names. A first group reported it as a neuronal Cdc2 like kinase (NCLK) characterized and cloned from rat brain c-DNA library as a Cdk that phosphorylates the lysine–serine–proline motif of neurofilaments. It was reported to have 58% amino acid sequence homology with mouse Cdk1 and 61% homology with human Cdk2. While looking for several Cdks, which play an important role in eukaryotic cell cycle, a second group found Cdk5/PSSALARE kinase (with an alpha C helix) among several other Cdks. A third group of scientists called the same molecule as brain proline-directed protein kinase (BPDK), reporting it in bovine brain with functional similarity to cdc2. In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules. Later in 1993, the nomenclature settled down to Cdk5 after identifying the 30 kDa protein subunit of the active enzyme.[1]
Structure
The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.[3]
Sequence similarities
The of the CDK5-p25 complex share homologuous sequences with the cell division protein kinase 5 and the with the cyclin-dependent kinase 5 activator (p35).
Biology
CDK5 is important in several aspects of neuronal development. It is implicated in cytoskeleton assembly and organization during axonal growth, neuronal differentiation and migration, synaptic activities in mature neurons and cell death in neurodegenerative diseases. CDK5 is also involved in the regulation of exocytosis and endocytosis of synaptic vesicles. It modulates signal transduction pathways regulating neuronal survival.[4] CDK5 is implicated in Alzheimer’s disease as it is involved in the hyperphosphorylation of the protein Tau that leads to neuronal cell death.
CDK5-p25 complex Control
The neurotoxic activator p25 activates CDK5 in one step by tethering the T-loop in the extended conformation and exposing CDK5's active site for kinase activity. When activated by p25, CDK5 causes the death of neurons, leading to neurodegenerative diseases. Deregulation of CDK5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases. Sometimes, p35, the activator of CDK5, is cleaved in p25 by a protease calcium-dependent, the calpain. This cut form of p35 (p25) is able to activate CDK5 and to trigger a modification of its cellular localization. It can increase its activity too. In Alzheimer’s disease or in the amyotrophic lateral sclerosis, when the ratio of p25 over p35 increases, it creates an hyperactivity of CDK5 which could hyperphosphorylate the protein Tau.[1]
References
- ↑ 1.0 1.1 1.2 Dhariwala FA, Rajadhyaksha MS. An unusual member of the Cdk family: Cdk5. Cell Mol Neurobiol. 2008 May;28(3):351-69. Epub 2008 Jan 8. PMID:18183483 doi:10.1007/s10571-007-9242-1
- ↑ PMCID: PMC50443
- ↑ 3.0 3.1 Zhang B, Su ZC, Tay TE, Tan VB. Mechanism of CDK5 activation revealed by steered molecular dynamics simulations and energy calculations. J Mol Model. 2010 Jun;16(6):1159-68. Epub 2009 Dec 15. PMID:20013135 doi:10.1007/s00894-009-0629-4
- ↑ Maccioni RB, Otth C, Concha II, Munoz JP. The protein kinase Cdk5. Structural aspects, roles in neurogenesis and involvement in Alzheimer's pathology. Eur J Biochem. 2001 Mar;268(6):1518-27. PMID:11248668
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