Dynamics of human CDK2 and CDK5 studied by computer simulations

OTYEPKA, Michal, Iveta BÁRTOVÁ, Zdeněk KŘÍŽ a Jaroslav KOČA. Dynamics of human CDK2 and CDK5 studied by computer simulations. In Cellular and Molecular Biology Letters. Wroclaw: Department of Genetic Biochemistry, Institute of Biochemistry, University of Wroclaw, 2005, s. 116-117. ISBN 1425-8153.

Základní údaje

• Originální název: Dynamics of human CDK2 and CDK5 studied by computer simulations
• Název česky: Studioum dynamiky CDK2 a CDK5 pomoci pocitacovych simulaci
• Autoři: OTYEPKA, Michal (203 Česká republika), Iveta BÁRTOVÁ (203 Česká republika, garant), Zdeněk KŘÍŽ (203 Česká republika) a Jaroslav KOČA (203 Česká republika).
• Vydání: Wroclaw, Cellular and Molecular Biology Letters, od s. 116-117, 2 s. 2005.
• Nakladatel: Department of Genetic Biochemistry, Institute of Biochemistry, University of Wroclaw

Další údaje

• Originální jazyk: angličtina
• Typ výsledku: Stať ve sborníku
• Obor: 10403 Physical chemistry
• Stát vydavatele: Česká republika
• Utajení: není předmětem státního či obchodního tajemství
• Organizační jednotka: Přírodovědecká fakulta
• ISBN: 1425-8153
• Klíčová slova anglicky: Molecular Dynamics; Interaction Energy; phosphorylation; CDK2; CDK5
• Štítky: CDK2, CDK5, Interaction Energy, molecular dynamics, phosphorylation

Anotace

Cyclin-dependent kinases (CDKs) control progression of the cell cycle, apoptosis, transcription, and differentiation in neuronal cells. CDK consists of two subunits, a catalytic subunit kinase and regulatory protein cyclin. Several CDKs (CDK1, CDK2, CDK4 and CDK6) show a dual mechanism of activation based on cyclin binding and phosphorylation of the activation loop. This model of activation, however, does not apply to CDK5, despite 60% sequence identity to CDK2. CDK5 is a unique member of the CDK family, as it is not activated by a cyclin. Instead, CDK5 activity is triggered by p35 and p39, proteins whose expression is limited to neurons and to a few other cell types [1]. Association of CDK5 with p35 or p39 is enough to full activate CDK5. Furthermore, CDK5 seems not to be activated by phosphorylation in the activation loop, even if this contains a potential phosphorylation site (Ser159, equivalent to Thr160 of CDK2) [2, 3]. Additionally, phosphorylation of the glycine-rich loop (G-loop) is inhibitory for CDK2 or CDK1 but it seems to be stimulatory for CDK5 [4]. The phosphorylation of Thr14 and Tyr15 in the G-loop is an important element of CDK regulation machinery. Structural aspects of that were recently studied on CDK2 using molecular dynamics [6, 7]. The Tyr15-CDK5 activatory phosphorylation structural mechanism has been speculated by Mapelli et al. [3] namely in context of roscovitine binding. The simulation on phosho-Tyr15-CDK5/p25/roscovitine complex shows that Tyr15 phosphorylation leads to Tyr15 exposure to solvent and also to G-loop shift. Phoshorylated Tyr15 behaves similarly to phospho-Tyr15 in CDK2, which causes also exposure of phosphate group to the solvent but produces also notable shift of the G-loop [7]. The analysis of interaction energies between roscovitine and CDK5 and pTyr15-CDK5 documents that Tyr15 phosphorylation has negligible influence on roscovitine binding in according to experimental observations [3]. Also, the interaction pattern between CDK/regulatory unit will be discussed in detail (specifita CDK-Cyklin).

Anotace česky

Cyclin-dependent kinases (CDKs) control progression of the cell cycle, apoptosis, transcription, and differentiation in neuronal cells. CDK consists of two subunits, a catalytic subunit kinase and regulatory protein cyclin. Several CDKs (CDK1, CDK2, CDK4 and CDK6) show a dual mechanism of activation based on cyclin binding and phosphorylation of the activation loop. This model of activation, however, does not apply to CDK5, despite 60% sequence identity to CDK2. CDK5 is a unique member of the CDK family, as it is not activated by a cyclin. Instead, CDK5 activity is triggered by p35 and p39, proteins whose expression is limited to neurons and to a few other cell types [1]. Association of CDK5 with p35 or p39 is enough to full activate CDK5. Furthermore, CDK5 seems not to be activated by phosphorylation in the activation loop, even if this contains a potential phosphorylation site (Ser159, equivalent to Thr160 of CDK2) [2, 3]. Additionally, phosphorylation of the glycine-rich loop (G-loop) is inhibitory for CDK2 or CDK1 but it seems to be stimulatory for CDK5 [4]. The phosphorylation of Thr14 and Tyr15 in the G-loop is an important element of CDK regulation machinery. Structural aspects of that were recently studied on CDK2 using molecular dynamics [6, 7]. The Tyr15-CDK5 activatory phosphorylation structural mechanism has been speculated by Mapelli et al. [3] namely in context of roscovitine binding. The simulation on phosho-Tyr15-CDK5/p25/roscovitine complex shows that Tyr15 phosphorylation leads to Tyr15 exposure to solvent and also to G-loop shift. Phoshorylated Tyr15 behaves similarly to phospho-Tyr15 in CDK2, which causes also exposure of phosphate group to the solvent but produces also notable shift of the G-loop [7]. The analysis of interaction energies between roscovitine and CDK5 and pTyr15-CDK5 documents that Tyr15 phosphorylation has negligible influence on roscovitine binding in according to experimental observations [3]. Also, the interaction pattern between CDK/regulatory unit will be discussed in detail (specifita CDK-Cyklin).

Návaznosti

• MSM0021622413, záměr: Název: Proteiny v metabolismu a při interakci organismů s prostředím

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Proteiny v metabolismu a při interakci organismů s prostředím