The Single Transmembrane Domains of Human Receptor Tyrosine Kinases Encode Self-Interactions

Finger, Carmen; Escher, Claudia; Schneider, Dirk

doi:10.1126/scisignal.2000547

Cited by 107 publications

(113 citation statements)

References 69 publications

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“…Supporting such a role for Ryk TM domain interactions in dimerization is a previous report that the wild-type TM sequence of Ryk, as well as those of many other human RTK-related proteins, showed significant activity in the TOXCAT assay (54). These results indicate that such interactions are an evolutionarily conserved general feature of the RTKs.…”

Section: Discussionmentioning

confidence: 54%

Homodimerization of the Wnt Receptor DERAILED Recruits the Src Family Kinase SRC64B

Petrova

Lahaye

Martiáñez

et al. 2013

Molecular and Cellular Biology

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Section: Discussionmentioning

confidence: 54%

Homodimerization of the Wnt Receptor DERAILED Recruits the Src Family Kinase SRC64B

Petrova

Lahaye

Martiáñez

et al. 2013

Molecular and Cellular Biology

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“…51 All 58 RTK transmembrane domains show a self-association propensity as measured by the TOXCAT assay. 52 VEGFR2 homodimerizes in the absence and presence of VEGFs. 50 VEGFRs form heterodimers as well: intact VEGFR2/VEGFR3 and VEGFR2/VEGFR1 dimers form as demonstrated by a number of biochemical techniques including PLA and co-immunoprecipitation.…”

Section: A New Model: Vegfr-nrp Interactions Outside Of the Extracellmentioning

confidence: 99%

VEGF-A121a binding to Neuropilins – A concept revisited

Sarabipour

Gabhann

2017

Cell Adhesion & Migration

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All known splice isoforms of vascular endothelial growth factor A (VEGF-A) can bind to the receptor tyrosine kinases VEGFR-1 and VEGFR-2. We focus here on VEGF-A121a and VEGF-A165a, two of the most abundant VEGF-A splice isoforms in human tissue1, and their ability to bind the Neuropilin co-receptors NRP1 and NRP2. The Neuropilins are key vascular, immune, and nervous system receptors on endothelial cells, neuronal axons, and regulatory T cells respectively. They serve as co-receptors for the Plexins in Semaphorin binding on neuronal and vascular endothelial cells, and for the VEGFRs in VEGF binding on vascular and lymphatic endothelial cells, and thus regulate the initiation and coordination of cell signaling by Semaphorins and VEGFs.2 There is conflicting evidence in the literature as to whether only heparin-binding VEGF-A isoforms – that is, isoforms with domains encoded by exons 6 and/or 7 plus 8a – bind to Neuropilins on endothelial cells. While it is clear that VEGF-A165a binds to both NRP1 and NRP2, published studies do not all agree on the ability of VEGF-A121a to bind NRPs. Here, we review and attempt to reconcile evidence for and against VEGF-A121a binding to Neuropilins. This evidence suggests that, in vitro, VEGF-A121a can bind to both NRP1 and NRP2 via domains encoded by exons 5 and 8a; in the case of NRP1, VEGF-A121a binds with lower affinity than VEGF-A165a. In in vitro cell culture experiments, both NRP1 and NRP2 can enhance VEGF-A121a-induced phosphorylation of VEGFR2 and downstream signaling including proliferation. However, unlike VEGFA-165a, experiments have shown that VEGF-A121a does not ‘bridge’ VEGFR2 and NRP1, i.e. it does not bind both receptors simultaneously at their extracellular domain. Thus, the mechanism by which Neuropilins potentiate VEGF-A121a-mediated VEGFR2 signaling may be different from that for VEGF-A165a. We suggest such an alternate mechanism: interactions between NRP1 and VEGFR2 transmembrane (TM) and intracellular (IC) domains.

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“…[1][2][3] Interestingly, several helical membrane proteins require a stable or transient association for their function, and recent evidence points to a ligand-independent association kinetics. 4,5 High resolution microscopy methods have revealed new insights into monomer-dimer equilibrium within membranes, 6 but the link between the molecular interactions and the population behavior is still missing.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamic and kinetic characterization of transmembrane helix association

Pawar

Deshpande

Gopal

et al. 2015

Phys. Chem. Chem. Phys.

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The transient dimerization of transmembrane proteins is an important event in several cellular processes and computational methods are being increasingly used to quantify their underlying energetics. Here, we probe the thermodynamics and kinetics of a simple transmembrane dimer to understand membrane protein association. A multi-step framework has been developed in which the dimerization profiles are calculated from coarse-grain molecular dynamics simulations, followed by meso-scale simulations using parameters calculated from the coarse-grain model. The calculated value of DG assoc is approx. À20 kJ mol À1 and is consistent between three methods. Interestingly, the meso-scale stochastic model reveals low dimer percentages at physiologically-relevant concentrations, despite a favorable DG assoc . We identify generic driving forces arising from the protein backbone and lipid bilayer and complementary factors, such as protein density, that govern self-interactions in membranes. Our results provide an important contribution in understanding membrane protein organization and linking molecular, nano-scale computational studies to meso-scale experimental data.

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The Single Transmembrane Domains of Human Receptor Tyrosine Kinases Encode Self-Interactions

Cited by 107 publications

References 69 publications

Homodimerization of the Wnt Receptor DERAILED Recruits the Src Family Kinase SRC64B

Homodimerization of the Wnt Receptor DERAILED Recruits the Src Family Kinase SRC64B

VEGF-A121a binding to Neuropilins – A concept revisited

Thermodynamic and kinetic characterization of transmembrane helix association

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