Sandbox 210: Difference between revisions
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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.<ref name="discovery" /> 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.<ref>PMID: 1639063</ref> 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.<ref>PMID: 1618840</ref> In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules.<ref>PMID: 1587865 </ref> Later in 1993, the nomenclature settled down to CDK5 after identifying the 30 kDa protein subunit of the active enzyme.<ref>PMID: 8253190</ref> | 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.<ref name="discovery" /> 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.<ref>PMID: 1639063</ref> 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.<ref>PMID: 1618840</ref> In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules.<ref>PMID: 1587865 </ref> Later in 1993, the nomenclature settled down to CDK5 after identifying the 30 kDa protein subunit of the active enzyme.<ref>PMID: 8253190</ref> | ||
==Structure== | ==Structure== | ||
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==Biology== | ==Biology== | ||
CDK5 is | ===Physiological Functions of CDK5=== | ||
CDK5 is in several aspects important for 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.<ref>PMID: 11248668</ref> CDK5 is implicated in Alzheimer’s disease as it is involved in the hyperphosphorylation of the protein Tau that leads to neuronal cell death. | |||
===Pathophysiology=== | |||
CDK5 is more and more believed to be linked to the etiopathology of neurodegenerative diseases like Alzheimer’s disease or amyotrophic lateral sclerosis (ALS). | |||
=== CDK5-p25 complex Control === | === 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. | 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 leads to hyperactivity of CDK5 which could hyperphosphorylate the protein Tau.<ref name="un" /> | ||
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 | |||
== External Resources == | == External Resources == | ||
