Related Experiment Videos
The structural biology of growth factor receptor activation
Nicholas J Harmer1, Dima Chirgadze, Kyung Hyun Kim
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
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.
Insights
Growth factors, essential for cell responses, bind receptors via their globular structure. Diverse binding mechanisms, including monomeric and dimeric forms, facilitate receptor activation and downstream signaling pathways.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Growth factors orchestrate crucial cellular processes like growth, differentiation, migration, and survival.
- Many growth factors utilize receptor tyrosine kinases (RTKs) for signal transduction, involving receptor dimerization and autophosphorylation.
- Understanding the precise mechanisms of growth factor-receptor interaction is key to deciphering cellular signaling.
Purpose of the Study:
- To investigate the role of growth factor architecture in receptor binding.
- To elucidate the diverse molecular mechanisms by which different growth factors (NGF, HGF/SF, FGF, insulin, IGF) interact with their respective receptors.
- To propose a general model for growth factor-receptor complex formation.
Main Methods:
- Comparative analysis of growth factor structures and their known receptor interactions.
- Review of existing literature on signaling cascades initiated by specific growth factors.
- Structural and functional characterization of growth factor-receptor complexes.
Main Results:
- The globular architecture of growth factors is critical for effective receptor binding.
- Nerve growth factor (NGF) forms a symmetrical hetero-hexameric complex (7SNGF) that dimerizes its receptor.
- Hepatocyte growth factor/scatter factor (HGF/SF) and fibroblast growth factor (FGF) likely bind receptors as dimers, often stabilized by heparan sulfate.
- Insulin and insulin-like growth factor (IGF) bind as monomers to pre-formed receptor dimers.
Conclusions:
- Growth factor-receptor binding involves diverse molecular strategies, including monomeric and dimeric interactions.
- Cooperative interactions between growth factors, receptor domains, and accessory molecules like heparan sulfate enhance binding specificity and complex formation.
- These findings provide a generalized framework for understanding signal transduction initiation by growth factors.