The Interface between Self-assembling Erythropoietin Receptor Transmembrane Segments Corresponds to a Membrane-spanning Leucine Zipper

Ruan, Wei; Becker, Verena; Klingmüller, Ursula; Langosch, Dieter

doi:10.1074/jbc.m309311200

Cited by 71 publications

(70 citation statements)

References 45 publications

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“…The noncovalent association of TM regions of proteins occurs via interactions of polar residues and/or the steric matching of complementary shaped surfaces such as with the glycophorin A motif (GXXXG motif) or by the interdigitation of bulky side chains analogous to the "knobs in holes" interactions of leucine zippers (31)(32)(33). The determinants of FcR␥ chain TM interaction with FcRs and other immunoreceptors is only partially understood and is significant because of the widespread expression of this subunit and its promiscuous incorporation into a number of receptors.…”

Section: Discussionmentioning

confidence: 99%

A Common Site of the Fc Receptor γ Subunit Interacts with the Unrelated Immunoreceptors FcαRI and FcϵRI

Wines

Trist

Ramsland

et al. 2006

Journal of Biological Chemistry

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The transmembrane (TM) region of the Fc receptor-␥ (FcR␥) chain is responsible for the association of this ubiquitous signal transduction subunit with many immunoreceptor ligand binding chains, making FcR␥ key to a number of leukocyte activities in immunity and disease. Some receptors contain a TM arginine residue that interacts with Asp-11 of the FcR␥ subunit, but otherwise the molecular basis for the FcR␥ subunit interactions is largely unknown. This study reports residues in the TM region of the FcR␥ subunit are important for association with the high affinity IgE receptor Fc⑀RI and a leukocyte receptor cluster member, the IgA receptor Fc␣RI. FcR␥ residue Leu-21 was essential for surface expression of Fc⑀RI␣/␥ 2 and Tyr-8, Leu-14, and Phe-15 contributed to expression. Likewise, detergent-stable FcR␥ association with Fc␣RI was also dependent on Leu-14 and Leu-21 and in addition required residues Tyr-17, Tyr-25, and Cys-26. Modeling the TM regions of the FcR␥ dimer indicated these residues interacting with both Fc␣RI and Fc⑀RI are near the interface between the two FcR␥ TM helices. Furthermore, the FcR␥ residues interacting with Fc␣RI form a leucine zipper-like interface with mutagenesis confirming a complementary interface comprising Fc␣RI residues Leu-217, Leu-220, and Leu-224. The dependence of these two nonhomologous receptor interactions on FcR␥ Leu-14 and Leu-21 suggests that all the associated Fc receptors and the activating leukocyte receptor cluster members interact with this one site. Taken together these data provide a molecular basis for understanding how disparate receptor families assemble with the FcR␥ subunit.The Fc receptor ␥ subunit (FcR␥) 2 is a ubiquitous signal transduction subunit widely found in hematopoietic cells and is present on macrophages, monocytes, dendritic cells, natural killer cells, platelets, eosinophils, mast cells, ␥␦ T cells, and CD4 ␣␤ effector T cells (1, 2). It is a promiscuous receptor subunit originally identified as a subunit of the high affinity IgE receptor Fc⑀RI (3) but is also associated with the ␥␦ TCR (4), the ␣␤ TCR (1, 2), DCAR (a novel C-type lectin immunoreceptor expressed on DC) (5, 6), mouse NKRP1A/C/F (7), NKp46 (8), the high affinity IgG receptor Fc␥RI (9), the low affinity IgG receptor Fc␥RIIIa (10), and the IgA receptor Fc␣RI (11,12). Fc␣RI, although a functional FcR, is a member of the leukocyte receptor cluster (LRC) whose genes are all encoded at 19q13.4 (13). A potentially charged TM residue in the Ig superfamily receptors is generally indicative of assembly with a small signal transduction molecule (14). The activating LRC receptors, Fc␣RI (11,12,15), the leukocyte Ig-like receptor A2 (LILR-A2, LIR7, ILT-1) (16), and the platelet collagen receptor glycoprotein VI (17, 18), NKp46 (8), and OSCAR (6), contain a TM arginine residue essential for interaction with FcR␥. Other than the TM arginine residue, it is not known if other TM residues of the activating LRC receptors are important in interacting with FcR␥. The TM regions of the FcRs, Fc⑀RI, Fc␥...

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Section: Discussionmentioning

confidence: 99%

A Common Site of the Fc Receptor γ Subunit Interacts with the Unrelated Immunoreceptors FcαRI and FcϵRI

Wines

Trist

Ramsland

et al. 2006

Journal of Biological Chemistry

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“…The interactions between RTK TM domains are often studies in the inner E. coli membrane using genetic two-hybrid methods. 16,17,[22][23][24] These assays (ToxR, TOXCAT, GALLEX) measure the interaction of membrane spanning helices linking a periplasmic maltose binding protein (MBP) with a cytosolic DNA-binding domain that is activated upon dimerization. These assays can report on both homodimer and heterodimer stabilities.…”

Section: Thermodynamics Of Rtk Tm Domain Dimerizationmentioning

confidence: 99%

Receptor tyrosine kinase transmembrane domains

Hristova

2010

Cell Adhesion & Migration

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“…The residues involved form a repeating heptad (abcdefg) pattern, wherein residues at the a and d positions constitute the core of the interfaces. 30,31 Although CAT activity was decreased or increased to a variable extent in Ala-and Leu-scanning mutagenesis methods, the extent of the variability correlated well with the distance from the potential dimerization interface. Consistent with this, our results showed that the sensitive Ibb TM residues (Ala125, Gln129, Leu132, Gly136, and His139) also occupied a and d positions of an (abcdefg) n leucine zipper motif.…”

Section: Discussionmentioning

confidence: 97%

The dimerization interface of the glycoprotein Ibβ transmembrane domain corresponds to polar residues within a leucine zipper motif

Wei

Liu

et al. 2011

Protein Science

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Experiments with the transmembrane (TM) domains of the glycoprotein (GP) Ib-IX complex have indicated that the associations between the TM domains of these subunits play an important role in the proper assembly of the complex. As a first step toward understanding these associations, we previously found that the Ibb TM domain dimerized strongly in Escherichia coli cell membranes and led to Ibb TM-CYTO (cytoplasmic domain) dimerization in the SDS-PAGE assay, while neither Iba nor IX TM-CYTO was able to dimerize. In this study, we used the TOXCAT assay to probe the Ibb TM domain dimerization interface by Ala-and Leu-scanning mutagenesis. Our results show that this interface is based on a leucine zipper-like heptad repeat pattern of amino acids. Mutating either one of polar residues Gln129 or His139 to Leu or Ala disrupted Ibb TM dimerization dramatically, indicating that polar residues might form part of the leucine zipperbased dimerization interface. Furthermore, these specific mutational effects in the TOXCAT assay were confirmed in the thiol-disulfide exchange and SDS-PAGE assays. The computational modeling studies further revealed that the most likely leucine zipper interface involves hydrogen bonding of Gln129 and electrostatic interaction of the His139 side chain. Correlation of computer modeling results with experimental mutagenesis studies on the Ibb TM domain may provide insights for understanding the role of the association of TM domains on the assembly of GP Ib-IX complex.

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The Interface between Self-assembling Erythropoietin Receptor Transmembrane Segments Corresponds to a Membrane-spanning Leucine Zipper

Cited by 71 publications

References 45 publications

A Common Site of the Fc Receptor γ Subunit Interacts with the Unrelated Immunoreceptors FcαRI and FcϵRI

A Common Site of the Fc Receptor γ Subunit Interacts with the Unrelated Immunoreceptors FcαRI and FcϵRI

Receptor tyrosine kinase transmembrane domains

The dimerization interface of the glycoprotein Ibβ transmembrane domain corresponds to polar residues within a leucine zipper motif

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