Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A

Markovic-Mueller, Sandra; Stuttfeld, Edward; Asthana, Mayanka; Weinert, T.; Bliven, Spencer; Goldie, Kenneth N.; Kisko, Kaisa; Capitani, Guido; Ballmer-Hofer, Kurt

doi:10.1016/j.str.2016.12.012

Cited by 81 publications

(70 citation statements)

References 57 publications

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“…Ligand-induced VEGFR homodimerization and activation VEGF ligands bind to the Ig-like domains 1-3 of their cognate VEGFRs, thereby inducing the activation of VEGFRs via symmetrical homotypic interactions between their membraneproximal Ig-like domains 4-7 (Leppanen et al, 2013;Markovic-Mueller et al, 2017;Yang et al, 2010). As an exception, VEGFB, which is a weak agonist of VEGFR1, does not appear to interact with domain 3 and cannot induce similar homotypic interactions (Anisimov et al, 2013).…”

Section: Vegf Pathway Activation Mechanismsmentioning

confidence: 99%

“…As an exception, VEGFB, which is a weak agonist of VEGFR1, does not appear to interact with domain 3 and cannot induce similar homotypic interactions (Anisimov et al, 2013). Conservation of the ligand-binding sites and the homotypic interactions provides the structural basis of VEGFR heterodimerization (Leppanen et al, 2013;Markovic-Mueller et al, 2017;Yang et al, 2010). VEGFRs can also form dimers in the absence of ligand, but ligand binding changes transmembrane domain conformation, thereby stimulating kinase domain phosphorylation (Sarabipour et al, 2016).…”

Section: Vegf Pathway Activation Mechanismsmentioning

confidence: 99%

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Vascular endothelial growth factor signaling in development and disease

2018

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Vascular endothelial growth factors (VEGFs) are best known for their involvement in orchestrating the development and maintenance of the blood and lymphatic vascular systems. VEGFs are secreted by a variety of cells and they bind to their cognate tyrosine kinase VEGF receptors (VEGFRs) in endothelial cells to elicit various downstream effects. In recent years, there has been tremendous progress in elucidating different VEGF/VEGFR signaling functions in both the blood and lymphatic vascular systems. Here, and in the accompanying poster, we present key elements of the VEGF/VEGFR pathway and highlight the classical and newly discovered functions of VEGF signaling in blood and lymphatic vessel development and pathology.

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Section: Vegf Pathway Activation Mechanismsmentioning

confidence: 99%

Section: Vegf Pathway Activation Mechanismsmentioning

confidence: 99%

Vascular endothelial growth factor signaling in development and disease

2018

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“…In such cases, the receptor's ECR is often composed primarily of immunoglobulin‐like domains, and ligand‐induced dimerization appears to be ligand‐mediated and relatively straightforward. Examples of this are seen with stem cell factor/Kit, 4 nerve growth factor/TrkA, 5 platelet‐derived growth factor (PDGF)/PDGF receptor, 6 vascular endothelial growth factor (VEGF)/VEGF receptors, 7 and fibroblast growth factor (FGF)/FGF receptors 8 …”

Section: Introductionmentioning

confidence: 99%

Insulin and epidermal growth factor receptor family members share parallel activation mechanisms

Ferguson

Lemmon

2020

Protein Science

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Insulin receptor (IR) and the epidermal growth factor receptor (EGFR) were the first receptor tyrosine kinases (RTKs) to be studied in detail. Both are important clinical targets-in diabetes and cancer, respectively. They have unique extracellular domain compositions among RTKs, but share a common module with two ligand-binding leucine-rich-repeat (LRR)-like domains connected by a flexible cysteine-rich (CR) domain (L1-CR-L2 in IR/domain, I-II-III in EGFR). This module is linked to the transmembrane region by three fibronectin type III domains in IR, and by a second CR in EGFR. Despite sharing this conserved ligand-binding module, IR and EGFR family members are considered mechanistically distinct-in part because IR is a disulfide-linked (αβ) 2 dimer regardless of ligand binding, whereas EGFR is a monomer that undergoes ligand-induced dimerization. Recent cryo-electron microscopy (cryo-EM) structures suggest a way of unifying IR and EGFR activation mechanisms and origins of negative cooperativity. In EGFR, ligand engages both LRRs in the ligand-binding module, "closing" this module to break intramolecular autoinhibitory interactions and expose new dimerization sites for receptor activation. How insulin binds the activated IR was less clear until now. Insulin was known to associate with one LRR (L1), but recent cryo-EM structures suggest that it also engages the second LRR (albeit indirectly) to "close" the L1-CR-L2 module, paralleling EGFR. This transition simultaneously breaks autoinhibitory interactions and creates new receptor-receptor contacts-remodeling the IR dimer (rather than inducing dimerization per se) to activate it. Here, we develop this view in detail, drawing mechanistic links between IR and EGFR. K E Y W O R D Sallostery, epidermal growth factor, insulin, negative cooperativity, receptor, receptor tyrosine kinase, structure

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“…The major regulators of angiogenesis are the vascular endothelial growth factors (VEGF‐A, VEGF‐B, VEGF‐C, and VEGF‐D) and the placenta growth factor (PlGF) . Their functions are performed through the specific binding and activation of two tyrosine kinase (TK) receptors, which were initially identified as receptors for VEGF‐A: VEGFR‐1 and VEGFR‐2 . Among the two receptors, VEGFR‐2 is the principal mediator of VEGF‐induced pathological angiogenic signaling; it is expressed on endothelial cells (ECs) and on circulating bone marrow–derived endothelial progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

Short PlGF‐derived peptides bind VEGFR‐1 and VEGFR‐2 in vitro and on the surface of endothelial cells

Caporale

Martin²,

Capasso

et al. 2019

Journal of Peptide Science

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The placental growth factor (PlGF), a member of VEGF family, plays a crucial role in pathological angiogenesis, especially ischemia, inflammation, and cancer. This activity is mediated by its selective binding to VEGF receptor 1 (VEGFR‐1), which occurs predominantly through receptor domains 2 and 3. The PlGF β‐hairpin region spanning residues Q87 to V100 is one of the key binding elements on the protein side. We have undertaken a study on the design, preparation, and functional characterization of the peptide reproducing this region and of a set of analogues where glycine 94, occurring at the corner of the hairpin in the native protein, is replaced by charged as well as hydrophobic residues. Also, some peptides with arginine 96 replaced by other residues have been studied. We find that the parent peptide weakly binds VEGFR‐1, but replacement of G94 with residues bearing H‐bond donating residues significantly improves the affinity. Replacement of R96 instead blocks the interaction between the peptide and the domain. The strongest affinity is observed with the G94H (peptide PlGF‐2) and G94W (peptide PlGF‐10) mutants, while the peptide PlGF‐8, bearing the R96G mutation, is totally inactive. The PlGF‐1 and PlGF‐2 peptides also bind the VEGFR‐2 receptors, though with a reduced affinity, and are able to interfere with the VEGF‐induced receptor signaling on endothelial cells. The peptides also bind VEGFR‐2 on the surface of cells, while PlGF‐8 is inactive. Data suggest that these peptides have potential applications as PlGF/VEGF mimic in various experimental settings.

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Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A

Cited by 81 publications

References 57 publications

Vascular endothelial growth factor signaling in development and disease

Vascular endothelial growth factor signaling in development and disease

Insulin and epidermal growth factor receptor family members share parallel activation mechanisms

Short PlGF‐derived peptides bind VEGFR‐1 and VEGFR‐2 in vitro and on the surface of endothelial cells

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