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Structural basis for the different stability and activity between the Cdk5 complexes with p35 and p39 activators
Taro Saito1, Masashi Yano1, Yusei Kawai1
1From the Department of Biological Sciences, Tokyo Metropolitan University, Minami-osawa, Hachioji, Tokyo 192-0397.
The Journal of Biological Chemistry
|October 3, 2013
Summary
The p39 activator
Area of Science:
- Neuroscience
- Molecular Biology
- Structural Biology
Background:
- Cyclin-dependent kinase 5 (Cdk5) is crucial for brain function, activated by p35 or p39.
- The p39-Cdk5 complex's function is poorly understood due to its instability.
- Instability arises from dissociation and loss of kinase activity in specific conditions.
Purpose of the Study:
- To investigate the structural basis for p39-Cdk5 instability.
- To understand the differences between p35-Cdk5 and p39-Cdk5 interactions.
Main Methods:
- Simulated the three-dimensional structure of the p39 activator (AD)-Cdk5 complex.
- Analyzed hydrogen bond networks in p35-Cdk5 and p39-Cdk5 complexes.
- Utilized substitution mutants to experimentally validate findings.
Main Results:
- Identified differences in hydrogen bonding between Cdk5 and its activators p35 and p39.
- Found that three specific amino acids in p39 (Gln, Gln, Pro) disrupt hydrogen bonds compared to p35 (Asp, Asn, Ser).
- Demonstrated that reduced hydrogen bonding in p39-Cdk5 contributes to its instability and altered properties.
Conclusions:
- The distinct hydrogen bond network in the C-terminal activation domain (AD) of p39 underlies its reduced stability compared to p35.
- Understanding these structural differences is key to elucidating p39-Cdk5 function.
- Experimental validation confirmed the role of hydrogen bonding in the differential properties of Cdk5 activators.
Keywords:
CDK (Cyclin-dependent Kinase)Cdk5Computer ModelingCyclinsHydrogen BondNeuronsSerine-Threonine Protein KinaseSubunit Interactionp35p39More Related Videos
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