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CDK5-p25 complexCDK5-p25 complex
CDK5 – Cyclin dependent Kinase 5CDK5 – Cyclin dependent Kinase 5
CDK5 is a serine-threonine kinase belonging to a large protein family: the cyclin dependent kinases. CDK5 gene has been mapped to chromosome seven. This CDK5 protein is a 33 kDa molecule with kinase activity when bound to its activators. Also known as proline-directed kinase, activated CDK5 phosphorylates the amino acids serine and threonine of its substrate that have a proline immediately downstream at position +1. The phosphorylation motif of CDK5's substrate is S/TPXK/R where S/T stands for serine respectively threonine, X can be any amino acid, P represents the obligatory proline and K/R stands for lysine or arginine, which are preferred at downstream position +3. Cyclin dependent 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]
HistoryHistory
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.[2] 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.[5] 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.[6] In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules.[7] Later in 1993, the nomenclature settled down to CDK5 after identifying the 30 kDa protein subunit of the active enzyme.[8]
StructureStructure
The 33 kDa- protein CDK5 consists of an eukaryotic catalytic domain (ePK) that is flanked by other domains involved in the regulation of ePK. CDK5 consists of a C-terminal domain that shows alpha-helical structure (C-lobe) and an N-terminal domain (N-lobe) consisting predominantly of a beta-sheet but also containing an alpha-helix, named alpha C-helix or PSAALRE, based on its amino acid sequence. Between N- and C-lobe the ATP-binding site is located in a deep cleft. Structural changes of the ePK domain are leading to different activation states of the kinase. Only a unique active conformation is able to transfer phosphate from an ATP-molecule onto a substrate. The activation loop or T-loop, a flexible stretch of approximately 20 amino acids between the interface of the C- and N-lobes, is the key for the control of these conformational changes. It provides the association of CDK5 with its activator proteins and is involved in the positioning of ATP. The activator protein of CDK5, p25, presents a cyclin-box fold domain, which is the structural motif found in the cyclins. More precisely, CDK5 binds p25 through its single cyclin box fold (CBF) around the CDK5's PSAALRE helix and the activation loop. The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.[9] Analyses of the crystal structures of CDK5/p25 show the existence of extensive electrostatic and Van Der Waals interactions between the β sheet, and a small loop following the C helix (f-loop) of CDK5, and an helix of p25. During the unbinding processes between CDK5 and p25, obvious conformational changes in the C helix and the T loop are observed. The C helix, together with the loop preceding the helix (the p-loop) apparently displaces from its original location towards the p25 side. The distances between the C-alpha carbon atoms of the tip amino acid of the p-loop (Gly43) and the starting amino acid of the C helix (Ser46) before and after pulling are 14.15 Å and 7.23 Å, respectively.[9]
Sequence similaritiesSequence 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).
BiologyBiology
Physiological functions of CDK5Physiological 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.[10] 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 ControlCDK5-p25 complex Control
Sometimes, p35, an 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 (ALS), when the ratio of p25 over p35 increases, it leads to hyperactivity of CDK5 which could hyperphosphorylate the protein Tau. 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 (ALS), Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases.[1]
External ResourceExternal Resource
ReferencesReferences
- ↑ 1.0 1.1 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
- ↑ 2.0 2.1 Hellmich MR, Pant HC, Wada E, Battey JF. Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10867-71. PMID:1279696
- ↑ Lew J, Huang QQ, Qi Z, Winkfein RJ, Aebersold R, Hunt T, Wang JH. A brain-specific activator of cyclin-dependent kinase 5. Nature. 1994 Sep 29;371(6496):423-6. PMID:8090222 doi:http://dx.doi.org/10.1038/371423a0
- ↑ Tang D, Yeung J, Lee KY, Matsushita M, Matsui H, Tomizawa K, Hatase O, Wang JH. An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. J Biol Chem. 1995 Nov 10;270(45):26897-903. PMID:7592934
- ↑ Meyerson M, Enders GH, Wu CL, Su LK, Gorka C, Nelson C, Harlow E, Tsai LH. A family of human cdc2-related protein kinases. EMBO J. 1992 Aug;11(8):2909-17. PMID:1639063
- ↑ Lew J, Beaudette K, Litwin CM, Wang JH. Purification and characterization of a novel proline-directed protein kinase from bovine brain. J Biol Chem. 1992 Jul 5;267(19):13383-90. PMID:1618840
- ↑ Ishiguro K, Takamatsu M, Tomizawa K, Omori A, Takahashi M, Arioka M, Uchida T, Imahori K. Tau protein kinase I converts normal tau protein into A68-like component of paired helical filaments. J Biol Chem. 1992 May 25;267(15):10897-901. PMID:1587865
- ↑ Kobayashi S, Ishiguro K, Omori A, Takamatsu M, Arioka M, Imahori K, Uchida T. A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubule. FEBS Lett. 1993 Dec 6;335(2):171-5. PMID:8253190
- ↑ 9.0 9.1 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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