Receptor tyrosine kinase transmembrane domains

Li, Edwin; Hristova, Kalina

doi:10.4161/cam.4.2.10725

Cited by 90 publications

(34 citation statements)

References 65 publications

(76 reference statements)

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“…Previous work has already revealed a difference in the effects of these two mutations; A391E increases FGFR3 activation by increasing dimerization, whereas G380R likely affects the structure of the dimer in the absence of ligand (8,9). Here, we demonstrate a second key difference between the two mutants.…”

Section: Receptor Pair (No Ligand)supporting

confidence: 50%

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FGFR3 Heterodimerization in Achondroplasia, the Most Common Form of Human Dwarfism

Shobnam

Wimley

et al. 2011

Journal of Biological Chemistry

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The G380R mutation in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) causes achondroplasia, the most common form of human dwarfism. Achondroplasia is a heterozygous disorder, and thus the affected individuals express both wild-type and mutant FGFR3. Yet heterodimerization in achondroplasia has not been characterized thus far. To investigate the formation of FGFR3 heterodimers in cellular membranes, we designed an FGFR3 construct that lacks the kinase domain, and we monitored the formation of inactive heterodimers between this construct and wild-type and mutant FGFR3. The formation of the inactive heterodimers depleted the pool of full-length receptors capable of forming active homodimers and ultimately reduced their phosphorylation. By analyzing the effect of the truncated FGFR3 on full-length receptor phosphorylation, we demonstrated that FGFR3 WT/G380R heterodimers form with lower probability than wild-type FGFR3 homodimers at low ligand concentration. These results further our knowledge of FGFR3-associated bone disorders.The G380R mutation in fibroblast growth factor receptor 3 (FGFR3) transmembrane (TM) 2 domain has been linked to achondroplasia, the most common form of human dwarfism (1). Achondroplasia, characterized by short stature, is a common (1 in 15,000 live births) autosomal dominant disorder that interferes with the maturation of the cartilage growth plate of long bones (2-4). The affected protein, FGFR3, is a receptor tyrosine kinase. Its activation, manifested in the autophosphorylation of its kinase domain, involves lateral dimerization and binding of FGF ligands and heparan sulfate (5, 6). Ligand binding increases receptor activation by stabilizing the dimers and perhaps altering the dimer structure (7-11).In cellular studies, the G380R mutation increases FGFR3 phosphorylation in the absence of ligand and at low ligand concentration (12-15). The increase, which is the likely cause for pathogenesis, has been linked to an increase in the phosphorylation of the unliganded dimer (13). However, FGFR3 dimerization does not appear affected by the G380R mutation, as both the wild-type FGFR3 and the G380R mutant show very similar cross-linking and dimerization propensities (13).Achondroplasia is a heterozygous disorder, and thus the affected individuals express both wild-type and mutant FGFR3. In this paper, we address the question whether mutant FGFR3 receptors heterodimerize with the wild type. Currently, the answer to this question is unknown. Most studies of FGFR3 activation thus far have focused on FGFR3 homodimers, because the detection of heterodimers is challenging. When both wild-type and mutant FGFR3 molecules are present in cells, three different dimeric species can co-exist as follows: 1) wild-type homodimers, 2) mutant homodimers, and 3) wildtype/mutant heterodimers (16). These dimers will be indistinguishable in many experiments, and their abundance will depend on the respective expression levels and on the dimerization propensities, which are unknown. Furthermore,...

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Section: Receptor Pair (No Ligand)supporting

confidence: 50%

“…Its activation, manifested in the autophosphorylation of its kinase domain, involves lateral dimerization and binding of FGF ligands and heparan sulfate (5,6). Ligand binding increases receptor activation by stabilizing the dimers and perhaps altering the dimer structure (7)(8)(9)(10)(11).…”

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confidence: 99%

FGFR3 Heterodimerization in Achondroplasia, the Most Common Form of Human Dwarfism

Shobnam

Wimley

et al. 2011

Journal of Biological Chemistry

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“…Understanding the factors determining helix-helix packing has therefore been the aim of several studies. [4][5][6][7][8][9][10][11][12] Most models developed to explain helix-helix packing rely on specic residue interactions between the helices. [8][9][10][11][12] These theories predict that specic residue interactions control the packing angle between the two a-helices in a TM helix pair.…”

Section: Introductionmentioning

confidence: 99%

Lipid mediated packing of transmembrane helices – a dissipative particle dynamics study

Benjamini

Smit

2013

Soft Matter

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Interactions of transmembrane (TM) helices play a key role in many cell processes. The configuration and cross angle these helices adopt are traditionally attributed to specific residue interactions. We present a different approach, in which specific residues are disregarded, and the role of the membrane in TM helix packing is investigated. We introduce a coarse-grained model of TM helices and obtain their characteristic configurations in the membrane both as a single helix and as paired helices. Our analysis shows that hydrophobic mismatch has a substantial effect in determining not only the tilt angles of TM helices but also the cross angles between helix pairs, for a large range of hydrophobic mismatches. We discuss the origin of this effect as well as the deviations from the common trend. Additionally, we explore the effect of hydrophobic mismatch on the Potential of Mean Force (PMF) between TM helices and discuss the importance of helical geometry in forming crossed configurations. Our observations suggest that hydrophobic mismatch must be taken into account when analyzing configurations of TM helix pairs. Hydrophobic mismatch through its effect on helix tilt can explain many cross-angle distribution features, making the role of specific interactions in determining helix pair configurations less significant.

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“…The transmembrane (TM) domains of RTKs have been shown to play an important thermodynamic role in the activation process (11, 12). In particular, isolated TM domains have been shown to dimerize in liposomes and in bacterial membranes, implying that the interactions between the TM domains help stabilize the full-length dimers (13–19).…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, the TM domains have been shown to interact even in the presence of the large RTK extracellular domains (20). RTK TM domains have been further proposed to play an important structural role in activation, as the interactions between them ensure that the kinase domains achieve the correct orientation and positioning (11, 12, 21–23). Since ErbB2/Neu does not require a ligand for activation, its TM domain has been intensively researched with the hope that these studies will reveal some of the physical requirements for ErbB2/Neu activation.…”

Section: Introductionmentioning

confidence: 99%

Strong dimerization of wild-type ErbB2/Neu transmembrane domain and the oncogenic Val664Glu mutant in mammalian plasma membranes

Placone

Piccolo

et al. 2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Here, we study the homodimerization of the transmembrane domain of Neu, as well as an oncogenic mutant (V664E), in vesicles derived from the plasma membrane of mammalian cells. For the characterization, we use a Förster resonance energy transfer (FRET)-based method termed Quantitative Imaging-FRET (QI-FRET), which yields the donor and acceptor concentrations in addition to the FRET efficiencies in individual plasma membrane-derived vesicles. Our results demonstrate that both the wild-type and the mutant are 100% dimeric, suggesting that the Neu TM helix dimerizes more efficiently than other RTK TM domains in mammalian membranes. Furthermore, the data suggest that the V664E mutation causes a very small, but statistically significant change in dimer structure.

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Receptor tyrosine kinase transmembrane domains

Cited by 90 publications

References 65 publications

FGFR3 Heterodimerization in Achondroplasia, the Most Common Form of Human Dwarfism

FGFR3 Heterodimerization in Achondroplasia, the Most Common Form of Human Dwarfism

Lipid mediated packing of transmembrane helices – a dissipative particle dynamics study

Strong dimerization of wild-type ErbB2/Neu transmembrane domain and the oncogenic Val664Glu mutant in mammalian plasma membranes

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