The structural biology of growth factor receptor activation
ABSTRACT Stimulation of cells by growth factors triggers cascades of signalling that result in cellular responses such as growth, differentiation, migration and survival. Many growth factors signal through receptor tyrosine kinases, leading to dimerization, trans-phosphorylation and activation of tyrosine kinases that phosphorylate components further downstream of the signal transduction cascade. Using insulin-like growth factor, nerve growth factor, hepatocyte growth factor and fibroblast growth factor as examples, we show that the globular architecture of the growth factors is essential for receptor binding. We describe how nerve growth factor (NGF) is a symmetrical dimer that binds four storage proteins (two alpha-NGF and two gamma-NGF) to give a symmetrical hetero-hexameric 7SNGF organised around the beta-NGF dimer. It binds the extracellular domains of two receptor molecules in a similar way, so dimerising the receptor. Hepatocyte growth factor/scatter factor (HGF/SF) probably binds its receptor as a dimer stabilised by interactions with heparan sulfate, and fibroblast growth factor (FGF) binds its receptor as a dimer cross-linked by heparan sulfate. Surprisingly, insulin and insulin-like growth factor (IGF) bind in the monomeric form to receptors that are already covalent dimers. We propose that, in general, weak binary interactions between growth factor and individual domains of receptors are enhanced by cooperative interactions with further receptor domains, and sometimes other components like heparan, to give rise to specific multi-protein/domain complexes.
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ABSTRACT: Control of structural flexibility is essential for the proper functioning of a large number of proteins and multiprotein complexes. At the residue level, such flexibility occurs due to local relaxation of peptide bond angles whose cumulative effect may result in large changes in the secondary, tertiary or quaternary structures of protein molecules. Such flexibility, and its absence, most often depends on the nature of interdomain linkages formed by oligopeptides. Both flexible and relatively rigid peptide linkers are found in many multidomain proteins. Linkers are thought to control favorable and unfavorable interactions between adjacent domains by means of variable softness furnished by their primary sequence. Large-scale structural heterogeneity of multidomain proteins and their complexes, facilitated by soft peptide linkers, is now seen as the norm rather than the exception. Biophysical discoveries as well as computational algorithms and databases have reshaped our understanding of the often spectacular biomolecular dynamics enabled by soft linkers. Absence of such motion, as in so-called molecular rulers, also has desirable functional effects in protein architecture. We review here the historic discovery and current understanding of the nature of domains and their linkers from a structural, computational, and biophysical point of view. A number of emerging applications, based on the current understanding of the structural properties of peptides, are presented in the context of domain fusion of synthetic multifunctional chimeric proteins.Biopolymers 01/2005; 80(6):736-46. DOI:10.1002/bip.20291 · 2.29 Impact Factor
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ABSTRACT: Systems biology integrates a variety of diverse approaches to the study of the cellular pathways comprised of protein networks. Following an initial ligand-receptor binding event, transduction of the signal is modified in a variety of ways via downstream protein interactions. Protein interactions can occur between two proteins or, alternatively, an interaction between two proteins can be facilitated by an adapter protein. Protein interactions can affect the spatial and temporal distribution of ligand-receptor complexes in cells, attenuating or prolonging signaling. With regard to gonadotropin receptors, protein interactions have been primarily studied in terms of desensitization and termination of signal transduction, or for their role in trafficking. The purpose of this review is to describe protein interactions that mediate gonadotropin receptor functions and to highlight some emerging interactions, as well as some of the caveats inherent in the attempt to uncover these pathways.Endocrine 05/2005; 26(3):241-7. DOI:10.1385/ENDO:26:3:241 · 3.53 Impact Factor