Platelet-derived growth factor (PDGF) is a dimeric glycoprotein composed of two monomers of an A chain (AA), B chain (BB), C chain (CC), D chain (DD) or a combination of A and B chains (AB). The monomers are inactive. These different properties determine the binding of PDGF to its receptor PDGF receptor (PDGFR). Since PDGF and PDGFR play a significant role in angiogenesis (and therefore tumor formation), the interactions of the two components are of strong interest to a number of scientists in the field.

Two types of PDGFRs have been identified. The first one is α-PDGFR; the second one is β-PDGFR. Since ligand binding leads to dimerization αα, ββ and αβ combinations are possible. Three of the five extracellular located immunoglobulin (IgG) domains serve as the ligand binding site. Fig. 1 demonstrates how the different receptors interact which a variety of ligands. PDGFR-αα and –αβ can bind PDGF-AB and –CC. PDGFR-ββ especially binds PDGF-DD and -BB. PDGFR-αα only binds PDGF-AA, while all three receptor types can bind to PDGF-BB.

 

Fig. 1 Activation patterns of PDGFR by different isoforms of PDGF. Extracellular five IgG domains are located; in the cytosol one split-kinase is present per monomer. The FGF receptor is also shown 1.

After activation by a ligand the receptor autophosphorylates its cytosolic kinase domains and after the binding of a number of cofactors the phosphorylation signal is transmitted in a receptor tyrosine kinase (RTK) specific manner with a focus on (1) MAPK and (2) PI3K pathways. The (1) MAPK pathway begins with the binding of adaptor protein Gbr2 to Sos, which in turn exchanges GDP for GTP on Ras. Ras phosphorylates Raf (MAPKKK) which subsequently transmits the signal to MAPKK and MAPK by the phosphorylation of Ser residues. In the following the activation of MAPK leads to the activation of cytoplasmic elements such as transcription factors which ultimately cause a cellular response. In the case of the (2) PI3K pathway PLCγ is recruited by activated RTK and synthesizes PIP3 and DAG, PIP3 activates Btk, Itk and Ser/Thr kinases PDK1 and Akt. At same time PIP3 can also activate the release of Ca²+ from intracellular depots. Ca²+ binds to calmodulin which in turn activates calmodulin-dependent protein kinases (CamKs). Other Ca²+ atoms together with DAG activate members of the PKC family which relays the signal further on to the nucleus where it causes a cellular response.

The whole intracellular signalling pathways can also be observed in an overview figure derived from Wikipedia which I have posted earlier.

Fig. 2 displays a molecular model of the recently identified interactions of PDGF with its receptor using the example of PDGF-B-βPDGFR.

 

Fig. 2 The conformational change of βPDGFR upon PDGF-B ligand binding is shown. (A) shows a structural comparison of bound dimeric PDGF-B (cyan) and the free dimer of the same molecule. Obvious are especially the conformational changes of the L1 and L3 loops of the ligand. (B) and (C) demonstrate the interactions of free and receptor bound PDGF-B molecules with the according amino acid residues on βPDGFR (pink) respectively 2.

 

1.  Demoulin, J. Growth Factor Receptors. de Duve Institute (2010) at <http://www.deduveinstitute.be/growth_factor_receptors.php&gt;

2.  Hye-Ryong Shim, A. et al. Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex. Proceedings of the National Academy of Sciences 107, 11307 -11312 (2010).

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Homology vs. Analogy

October 8, 2010

Inspired by Banksy and the movie “Exit through the giftshop”.