The order and timing of cell cycle events is controlled by changing substrate specificity and different activity thresholds of cyclin-dependent kinases (CDK). However, it is not understood how a single protein kinase can trigger hundreds of switches in a sufficiently time-resolved fashion. We show that the cyclin-Cdk1-Cks1-dependent phosphorylation of multisite targets in Saccharomyces cerevisiae is controlled by key substrate parameters including distances between phosphorylation sites, the distribution of serines and threonines as phospho-acceptors, and the positioning of cyclin-docking motifs. The component mediating the key interactions in this process is Cks1, the phospho-adaptor subunit of the cyclin-Cdk1-Cks1 complex. We propose that variation of these parameters within the networks of phosphorylation sites in different targets provides a wide range of possibilities for the differential amplification of Cdk1 signals, providing a mechanism to generate a wide range of thresholds in the cell cycle.
The interaction between components of the extracellular matrix and the cell surface of cardiac myocytes appears to be regulated in part by receptors belonging to the integrin superfamily. The expression of the integrins was investigated at different stages of development of the heart as well as during cardiac hypertrophy. The characterization of the membrane proteins showed that a beta 1-integrin and associated alpha-chains were responsible for the interaction with collagen, laminin, and fibronectin. Immunoprecipitation data indicated that the presence of specific alpha-chains varied with development. These data were correlated with the ability of the isolated myocytes to attach to specific components of the extracellular matrix. The expression of the alpha 1-chain was prominently associated with the recognition of interstitial collagens. The presence of the alpha 1-chain was also associated with stages when collagen synthesis was increased, especially during fetal and neonatal growth and cardiac hypertrophy. Immunohistochemical localization with the antiserum against beta 1-integrin demonstrated its specific localization near the Z lines of cardiac myocytes. The localization both in vitro and in vivo indicated that the beta 1-integrin may play a role in myofibrillogenesis during development. The present immunohistochemical, cell adhesion, and biochemical data clearly indicate that integrins play a major role in the regulation of the interaction between cardiac myocytes and the extracellular matrix during development and disease.
Cks is an evolutionarily conserved protein that regulates cyclin-dependent kinase (Cdk) activity. Clarifying the underlying mechanisms and cellular contexts of Cks function is critical, as Cks is essential for proper cell growth, and its overexpression has been linked to cancer. We observe that budding yeast Cks associates with select phosphorylated sequences in cell cycle regulatory proteins. We characterize the molecular interactions responsible for this specificity and demonstrate that Cks enhances Cdk activity in response to specific priming phosphosites. Identification of the binding consensus sequence allows us to identify putative Cks-directed Cdk substrates and binding partners. We characterize novel Cks binding sites in the mitotic regulator Wee1 and discover a novel role for Cks in regulating Cdk activity at mitotic entry. Together our results portray Cks as a multifunctional phosphoadaptor that serves as a specificity factor for Cdk activity.
We report a method for creating hybrid organic-inorganic “nanoflowers” using calcium or copper ions as the inorganic component and a recombinantly expressed elastin-like polypeptide (ELP) as the organic component. Polypeptides provide binding sites for the dynamic coordination with metal ions, and then such noncovalent complexes become nucleation sites for primary crystals of metal phosphates. We have shown that the interaction between the stimuli-responsive ELP and Ca2+ or Cu2+, in the presence of phosphate, leads to the growth of micrometer-sized particles featuring nanoscale patterns shaped like flower petals. The morphology of these flower-like composite structures is dependent upon the temperature of growth and has been characterized by scanning electron microscopy. The composition of nanoflowers has also been analyzed by energy-dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, and X-ray diffraction. The temperature-dependent morphologies of these hybrid nanostructures, which arise from the controllable phase transition of ELPs, hold potential for morphological control of biomaterials in emerging applications such as tissue engineering and biocatalysis.
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