p27 structure, with highlighted specific domains and amino acid residues playing a key role in the interaction with/activity modulation of CDK-containing complex. CRNA, cell cycle-related neuronal apoptosis. This attenuates the CDK5 cell division restraining activity and might stimulate apoptosis. In response to cell exposure to Aβ(1−42) peptide (an amyloid derived peptide), p27 seems to act as scaffold in favoring the association of CDK5 and Cyclin D1 in a trimeric complex with p27 itself that does not translocate in the nucleus, but hampers CDK5 interaction with its physiological partner and activator p35. Its canonical interacting partner is p35 and when formed the complex p35/CDK5 is nuclear and active. The kinase CDK5 plays important roles in cell cycle arrest of postmitotic neurons. Subsequently, the ejection of the 3 10-helix is favored and the catalytic cleft of CDK2 becomes structurally very similar to that of the active Cyclin A/phospho-CDK2 complex. The phosphorylation of Tyr88 in the 3 10-helix disrupts the inhibitory interactions of p27 with CDK2 and allows the reestablishment of specific interfacial contacts between Cyclin A and CDK2, as in the active Cyclin A/CDK2 binary complex. The panel highlights the binding of p27 KID to the Cyclin A and to the kinase CDK2 When working as inhibitor, p27 is strongly tethered to CDK2, with its 3 10-helix allocated into the catalytic cleft of CDK2 to block ATP access and, then, to inhibit the kinase. p27 interaction with Cyclin A/CDK2 containing complex is recapitulated (see the text for further details). When bound to p27, the Cyclin D/CDK4 is resistant to inhibition by palbociclib, a specific Cyclin-D/CDK4 inhibitor now in clinical trials for high-risk ER +/HER2 − breast cancer. The modification of Tyrosine 74 (88) (P in red) by non-receptor tyrosine kinases (nRTKs) weakens the affinity of p27 for CDK4 which is then free to allocate the ATP in its specific ATP-binding site, allowing the full activation of the kinase complex. ( A) p27 binds sequentially Cyclin D and CDK4, facilitating the formation of the kinase complex. The sequence of the events is reported in detail in the text. The scheme summarizes some of p27 interaction with different Cyclin/CDK heterodimers. In this review, we look at p27 Kip1 properties and ascribe part of its heterogeneous functions to the ability to act as an anchor or scaffold capable to participate in the construction of different platforms for modulating cell response to extracellular signals and allowing adaptation to environmental changes.ĬDK Rho GTPase cyclin cytoskeleton intrinsically unstructured protein p27Kip1 scaffold protein αTAT1. p27 Kip1 belongs to the family of the intrinsically unstructured proteins and thus it is endowed with a large flexibility and numerous interactors, only partially identified. As a matter of fact, the protein is phosphorylated, ubiquitinated, SUMOylated, O-linked N-acetylglicosylated and acetylated on different residues. Several factors modulate p27 Kip1 activities, including its level, cellular localization and post-translational modifications. Recently, other important p27 Kip1 functions have been described, including the regulation of cell motility and migration, the control of cell differentiation program and the activation of apoptosis/autophagy. It also regulates G2/M progression and cytokinesis completion, via CDK-dependent or -independent mechanisms. The Cyclin-dependent kinase (CDK) regulator p27 Kip1 is a gatekeeper of G1/S transition.
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