Two PDGF-B chain residues, arginine 27 and isoleucine 30, mediate receptor binding and activation.

Clements, John M.; Bawden, Lindsay J.; Bloxidge, R.E.; Catlin, Graham; Cook, A; Craig, Stewart; Drummond, Alan H.; Edwards, Richard M.; Fallon, A.; Green, D.R.

doi:10.1002/j.1460-2075.1991.tb04988.x

Cited by 55 publications

(41 citation statements)

References 35 publications

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“…The PDGF-B/PDGFRβ interface can be used to reconcile a wide array of previous mutagenesis and deletion mapping data on PDGF-PDGFR interactions (18)(19)(20)(21)(22), which identified the L1, L2, and L3 loops as part of the receptor-binding epitope. In particular, Clements et al mutated throughout the PDGF-B surface, and found that most mutations have only minor effects on receptor binding, but that Arg27 and Ile30 are two major determinants for PDGF-B:PDGFRβ interaction (19).…”

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confidence: 95%

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Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex

Shim

Liu

Focia

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

161

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Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are prototypic growth factors and receptor tyrosine kinases which have critical functions in development. We show that PDGFs share a conserved region in their prodomain sequences which can remain noncovalently associated with the mature cystine-knot growth factor domain after processing. The structure of the PDGF-A/propeptide complex reveals this conserved, hydrophobic association mode. We also present the structure of the complex between PDGF-B and the first three Ig domains of PDGFRβ, showing that two PDGF-B protomers clamp PDGFRβ at their dimerization seam. The PDGF-B:PDGFRβ interface is predominantly hydrophobic, and PDGFRs and the PDGF propeptides occupy overlapping positions on mature PDGFs, rationalizing the need of propeptides by PDGFs to cover functionally important hydrophobic surfaces during secretion. A large-scale structural organization and rearrangement is observed for PDGF-B upon receptor binding, in which the PDGF-B L1 loop, disordered in the structure of the free form, adopts a highly specific conformation to form hydrophobic interactions with the third Ig domain of PDGFRβ. Calorimetric data also shows that the membrane-proximal homotypic PDGFRα interaction, albeit required for activation, contributes negatively to ligand binding. The structural and biochemical data together offer insights into PDGF-PDGFR signaling, as well as strategies for PDGF-antagonism.crystallography | receptor tyrosine kinase | signal transduction

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confidence: 95%

“…In particular, Clements et al mutated throughout the PDGF-B surface, and found that most mutations have only minor effects on receptor binding, but that Arg27 and Ile30 are two major determinants for PDGF-B:PDGFRβ interaction (19). In the complex, Arg27, as discussed above, forms hydrogen bonds with the main chain oxygen atom of PDGFRβ Glu241.…”

mentioning

confidence: 99%

Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex

Shim

Liu

Focia

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

161

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“…The identification of specific residues in PDGF that are responsible for receptor activation has been intensively investigated by several laboratories (29)(30)(31)(32)(33). The (35).…”

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confidence: 99%

Cellular transformation by a transmembrane peptide: structural requirements for the bovine papillomavirus E5 oncoprotein.

Meyer

Webster

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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The ES oncoprotein of bovine papillomavirus, only 44 amino adds long, occurs as a disulfide-bonded transmembrane dimer. This remarkable oncoprotein stimulates signal transduction.through activation of the plateletderived growth factor (PDGF) receptor, and E5 exhibits limited amino acid sequence similarit with PDGF. Results presented here sugest that a key feature of the hydrophobic transmembrane domain is an amino acid side chain that participates in interhelical hydrogen bond formation. These data are reminiscent of the activated neu oncogene, in which a point mutation in the membrane domain leads to lipndindependent dimerization and activation of a receptor tyrosine kinase. Signfcantly, the tranmembrane domain of E5 can be largely replaced by the transmembrane domain from the activated neu receptor tyrosine kinase. Extensive mutageneis defines the minimal structural features required for transformation by the ES oncoprotein as, first, the ability to dimerize and, second, presentation ofa negatively charged residue at the extralular side of the membrane. The biological activity of ES mutants that lack most amino acid residues similar to PDGF snggests that ES and PDGF activate the PDGF receptor by disnct mechanisms.Bovine papillomavirus type I (BPV) typifies the fibropapilloma viruses, which transform fibroblasts in vitro and lead to development of fibrosarcomas in their host. In contrast, the human papillomaviruses infect epithelial cells and are strongly implicated in carcinomas of the cervix and respiratory tract (1). The fibroblast-transforming function of BPV is due to a small open reading frame, designated E5, encoding a 44-residue protein that forms membrane-associated disulfide-bonded dimers (2-6). Recent work has demonstrated that the E5 oncoprotein activates the platelet-derived growth factor (PDGF) P-receptor (7,8) and may display functional similarity with the human T-lymphotropic virus type I p12' protein (9).Inspection of the amino acid sequence of the E5 oncoprotein reveals two distinct domains (2-6): an extremely hydrophobic N-terminal domain, residues 1-32, and a hydrophilic C-terminal domain, residues 33-44. Several studies have led to the conclusion that the E5 oncoprotein is membraneanchored with a type II orientation, with the N terminus intracellular and the C terminus extracellular (10). In addition, the hydrophobic domain of E5 can function as a signal-anchor domain, indistinguishable from signal-anchor domains of well-characterized type II proteins such as neuraminidase, transferrin receptor, or asialoglycoprotein receptor (11).In this work, we describe the minimal structural features required for biological transforming activity by a transmembrane peptide. The results presented here suggest that E5 and PDGF activate the PDGF receptor by fundamentally distinct mechanisms. ES/neu Substitution Mutant. Degenerate oligonucleotides were synthesized that would encode a pool of E5/neu transmembrane recombinants in which the 44 residues would be derived as follows: 1-5 from E5, 6-10 from...

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“…Thus, each subunit consists of two loops (loops 1 and 3) pointing in one direction and another (loop 2) pointing in the other direction. Mutational analyses have revealed that amino acid residues in loops 1 and 3 are important for receptor binding [3][4][5][6]. Also loop 2, which is located close to loops 1 and 3 in the other subunit in the dimer, is important for receptor binding, in particular for binding to the I~-receptor [4,7].…”

Section: Introductionmentioning

confidence: 99%

Identification of three amino acid residues in the B‐chain of platelet‐derived growth factor with different importance for binding to PDGF α‐ and β‐receptors

et al. 1996

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The B-chain homodimer isoform of platelet-derived growth factor (PDGF) binds with high affinity both to ~-and to IS-receptors. In order to localize amino acid residues in PDGF-BB of differential importance for the binding to the two receptors, PDGF-BB mutants were analyzed in which single amino acid residues were changed to alanine residues. We found that Phe-118 in loop 1 of the PDGF B-chain is crucial for binding to both receptors, and that the surrounding amino acids, Asn-117 and Leu-119, appear to be important primarily for binding to the [~-receptor. In contrast, Lys-161 in loop 3 was found to be more important for binding to a-receptors than receptors. Previous studies have shown that the receptor binding epitopo of PDGF-BB is composed mainly of loops 1 and 3; the findings of the present study show that the cz-and IS-receptors interact with different amino acid residues in these regions.

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Two PDGF-B chain residues, arginine 27 and isoleucine 30, mediate receptor binding and activation.

Cited by 55 publications

References 35 publications

Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex

Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex

Cellular transformation by a transmembrane peptide: structural requirements for the bovine papillomavirus E5 oncoprotein.

Identification of three amino acid residues in the B‐chain of platelet‐derived growth factor with different importance for binding to PDGF α‐ and β‐receptors

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