title: Evaluation of the interaction of cyclin-dependent kinase 5 with activator p25 and with p25-derived inhibitor CIP.
abstract: A high-affinity inhibitor protein called CIP, produced by small truncations of p35, was experimentally identified. P35 is a physiological activator of the cyclin-dependent kinase cdk5. P25 is derived from proteolytic truncation of p35 within "stressed" neurons, and it is associated with the hyperphosphorylation of specific neuronal proteins, typically occurring in neurodegenerative diseases such as Alzheimer's. Here, we report a study of the binding mechanisms of the cdk5-p25 and cdk5-CIP complexes. This provides a better understanding of the source of the inhibitory activity of the protein CIP. We use a geometry-based technique to test the hypothesis that p25's truncation increases the flexibility of CIP and thus prevents cdk5 from reaching its active conformation. Our study is based on a geometry-based alignment algorithm, which aligns two given protein conformations with respect to their interfaces. Our results support the flexibility hypothesis and will be used as a basis for targeted molecular dynamics simulations.
authors.affiliation: National Institute of Standards and Technology, Gaithersburg, Maryland 20899, USA. cardone@nist.gov
authors.forename: Antonio
authors.initials: A
authors.lastname: Cardone
authors.forename: R Wayne
authors.initials: RW
authors.lastname: Albers
authors.forename: Ram D
authors.initials: RD
authors.lastname: Sriram
authors.forename: Harish C
authors.initials: HC
authors.lastname: Pant
mesh_terms: D000465:Algorithms; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5