Journal: J Mol Biol / Year: 2015 Title: Structure of Full-Length Human PDGFRβ Bound to Its Activating Ligand PDGF-B as Determined by Negative-Stain Electron Microscopy. Authors: Po-Han Chen / Vinzenz Unger / Xiaolin He / Abstract: Members of the receptor tyrosine kinases (RTKs) regulate important cellular functions such as cell growth and migration, which are key steps in angiogenesis, in organ morphogenesis and in the ...Members of the receptor tyrosine kinases (RTKs) regulate important cellular functions such as cell growth and migration, which are key steps in angiogenesis, in organ morphogenesis and in the unregulated states, cancer formation. One long-standing puzzle regarding RTKs centers on how the extracellular domain (ECD), which detects and binds to growth factors, is coupled with the intracellular domain kinase activation. While extensive structural works on the soluble portions of RTKs have provided critical insights into RTK structures and functions, lack of a full-length receptor structure has hindered a comprehensive overview of RTK activation. In this study, we successfully purified and determined a 27-Å-resolution structure of PDGFRβ [a full-length human platelet-derived growth factor receptor], in complex with its ligand PDGF-B. In the ligand-stimulated complex, two PDGFRβs assemble into a dimer via an extensive interface essentially running along the full-length of the receptor, suggesting that the membrane-proximal region, the transmembrane helix and the kinase domain of PDGFRβ are involved in dimerization. Major structural differences are seen between the full-length and soluble ECD structures, rationalizing previous experimental data on how membrane-proximal domains modulate receptor ligand-binding affinity and dimerization efficiency. Also, in contrast to the 2-fold symmetry of the ECD, the intracellular kinase domains adopt an asymmetric dimer arrangement, in agreement with prior observations for the closely related KIT receptor. In essence, the structure provides a first glimpse into how platelet-derived growth factor receptor ECD, upon ligand stimulation, is coupled to its intracellular domain kinase activation.
History
Deposition
Aug 12, 2015
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Header (metadata) release
Sep 23, 2015
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Map release
May 4, 2016
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Update
May 4, 2016
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Current status
May 4, 2016
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Protein or peptide: Platelet-derived growth factor receptor beta
Protein or peptide: Platelet-derived growth factor-BB
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Supramolecule #1000: human PDGF-B bound to PDGFR-Beta
Supramolecule
Name: human PDGF-B bound to PDGFR-Beta / type: sample / ID: 1000 Details: The sample is cross-linked via the GraFix method after the gel filtration step. Oligomeric state: a PDGF-B dimer bound to two PDGFR-Beta / Number unique components: 2
Molecular weight
Experimental: 300 KDa / Theoretical: 300 KDa / Method: gel filtration and SDS-PAGE analysis
Name: Platelet-derived growth factor receptor beta / type: protein_or_peptide / ID: 1 / Name.synonym: PDGFR-Beta Details: N-terminal Flag tag is attached after a secretion signal derived from Gaussia luciferase. Number of copies: 2 / Oligomeric state: Dimer / Recombinant expression: Yes
Source (natural)
Organism: Homo sapiens (human) / synonym: Human / Location in cell: plasma membrane
Initial models are reconstructed by RCT. Visual inspection of similar classes were pooled, and one initial model was used as an input model for 3D classification into three classes using RELION.
Final reconstruction
Algorithm: OTHER / Resolution.type: BY AUTHOR / Resolution: 27.0 Å / Resolution method: OTHER / Software - Name: XMIPP, RELION / Number images used: 4234
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