The structure of the CD3 ζζ transmembrane dimer in POPC and raft-like lipid bilayer: A molecular dynamics study

Petruk, Ariel Alcides; Varriale, Sonia; Coscia, Maria Rosaria; Mazzarella, L.; Merlino, Antonello; Oreste, Umberto

doi:10.1016/j.bbamem.2013.07.019

Cited by 10 publications

(10 citation statements)

References 48 publications

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“…These studies showed consistently that the extracellular CD3 domains are located underneath the TCR␣␤ chains (10 -12) but disagreed on proposed docking sites of the CD3 subunits to TCR␣␤ (11,12). Although the conformation of the small extracellular portion (9 residues) of is not known, the association of the helical transmembrane segments of 2 in micelles was determined by NMR (13) and refined in molecular dynamics simulations within a lipid bilayer (14,15). A model for the assembly of all eight transmembrane domains in the intact TCR complex has been proposed based on charge-pairing interactions within the bilayer (16).…”

Section: Interactions Between Lipid Bilayers and The Membrane-proximamentioning

confidence: 99%

The cytosolic domain of T-cell receptor ζ associates with membranes in a dynamic equilibrium and deeply penetrates the bilayer

Zimmermann¹,

Eells²,

Heinrich

et al. 2017

Journal of Biological Chemistry

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Interactions between lipid bilayers and the membrane-proximal regions of membrane-associated proteins play important roles in regulating membrane protein structure and function. The T-cell antigen receptor is an assembly of eight single-pass membrane-spanning subunits on the surface of T lymphocytes that initiates cytosolic signaling cascades upon binding antigens presented by MHC-family proteins on antigen-presenting cells. Its ζ-subunit contains multiple cytosolic immunoreceptor tyrosine-based activation motifs involved in signal transduction, and this subunit by itself is sufficient to couple extracellular stimuli to intracellular signaling events. Interactions of the cytosolic domain of ζ (ζ) with acidic lipids have been implicated in the initiation and regulation of transmembrane signaling. ζ is unstructured in solution. Interaction with acidic phospholipids induces structure, but its disposition when bound to lipid bilayers is controversial. Here, using surface plasmon resonance and neutron reflection, we characterized the interaction of ζ with planar lipid bilayers containing mixtures of acidic and neutral lipids. We observed two binding modes of ζ to the bilayers in dynamic equilibrium: one in which ζ is peripherally associated with lipid headgroups and one in which it penetrates deeply into the bilayer. Such an equilibrium between the peripherally bound and embedded forms of ζ apparently controls accessibility of the immunoreceptor tyrosine-based activation signal transduction pathway. Our results reconcile conflicting findings of the ζ structure reported in previous studies and provide a framework for understanding how lipid interactions regulate motifs to tyrosine kinases and may regulate the T-cell antigen receptor biological activities for this cell-surface receptor system.

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Section: Interactions Between Lipid Bilayers and The Membrane-proximamentioning

confidence: 99%

The cytosolic domain of T-cell receptor ζ associates with membranes in a dynamic equilibrium and deeply penetrates the bilayer

Zimmermann¹,

Eells²,

Heinrich

et al. 2017

Journal of Biological Chemistry

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“…Streptavidin-binding peptide (SBP)-tagged CD16A was cotranslated with either HA-tagged FceR1γ or HA-CD247 in the presence of ER-derived microsomes and 35 S-labeled methionine/cysteine, and then complex formation was quantitated in coimmunoprecipitation experiments (Fig. 1C and Fig.…”

Section: Cd16amentioning

confidence: 99%

Transmembrane features governing Fc receptor CD16A assembly with CD16A signaling adaptor molecules

Blázquez-Moreno

Park

et al. 2017

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

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Many activating immunoreceptors associate with signaling adaptor molecules like FceR1γ or CD247. FceR1γ and CD247 share high sequence homology and form disulphide-linked homodimers that contain a pair of acidic aspartic acid residues in their transmembrane (TM) domains that mediate assembly, via interaction with an arginine residue at a similar register to these aspartic acids, with the activating immunoreceptors. However, this model cannot hold true for receptors like CD16A, whose TM domains do not contain basic residues. We have carried out an extensive site-directed mutagenesis analysis of the CD16A receptor complex and now report that the association of receptor with the signaling adaptor depends on a network of polar and aromatic residues along the length of the TM domain. Molecular modeling indicates that CD16A TM residues F 202 , D 205, and T 206 form the core of the membrane-embedded trimeric interface by establishing highly favorable contacts to the signaling modules through rearrangement of a hydrogen bond network previously identified in the CD247 TM dimer solution NMR structure. Strikingly, the amino acid D 205 also regulates the turnover and surface expression of CD16A in the absence of FceR1γ or CD247. Modeling studies indicate that similar features underlie the association of other activating immune receptors, including CD64 and FceR1α, with signaling adaptor molecules, and we confirm experimentally that equivalent F, D, and T residues in the TM domain of FceR1α markedly influence the biology of this receptor and its association with FceR1γ. dim natural killer (NK) cells, subsets of monocytes, dendritic cells, and rare T cells. FcγRIIIB (CD16B) is encoded by a distinct gene and is preferentially expressed by neutrophils (1). CD16B is a GPI-anchored glycoprotein whereas CD16A is a type 1 membrane glycoprotein with a single transmembrane (TM) domain and a short cytoplasmic tail whose expression at the cell surface depends on association with the signaling adaptor molecules CD247 (TCRζ) and/or FceR1γ (1-4). First discovered as components of the TCR:CD3 complex and the high affinity receptor for IgE, respectively (5-7), CD247 and FceR1γ are integral membrane proteins that have subsequently been found to be obligate signaling adaptors for many immunoreceptors in different cell types. Both adaptors have very short extracellular domains and cytoplasmic tails that contain immunoreceptor tyrosinebased activating motifs (ITAMs) for signal transduction. Moreover, both CD247 and FceR1γ form dimers in the endoplasmic reticulum (ER) that are stabilized by a disulphide bond at the junction between the extracellular and TM domains so that, at the cell surface, CD247 and FceR1γ in complex with their client receptors are dimeric. In general, the receptors known to associate with CD247 and FceR1γ have short intracellular tails and thus are completely dependent on these adaptors to signal, although phosphorylation of a protein kinase C (PKC) motif in the cytoplasmic tail of CD16A can modulate the outcome of receptor ...

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“…Indeed, changes in the tilt angle of a transmembrane domain as well as changes in the NMR structure between pure lipid and raft-like bilayers have been reported for other membrane receptors [93,94]. The simulations presented here support the studies that suggest the membrane composition heavily influences the structure and behaviour of proteins embedded in the membrane.…”

Section: 7supporting

confidence: 76%

Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

Corbett¹

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The ability of a cell to recognise and respond to external stimuli is essential for cell survival and growth. Type-I cytokine receptors regulate many inflammatory, homeostatic, and growth and development signalling pathways. For example, the erythropoietin receptor is the main driver of red blood cell production from stem cells. All type-I cytokine receptors consist of an extracellular ligandbinding domain, a single helical transmembrane domain and an intracellular domain that associates with kinase/transcription factor signalling pathway, for example the JAK2/STAT5 pathway. Despite being extensively studied and structures of the extracellular domains of many of these receptors being known, the precise mechanism by which these receptors couple the event of ligand-binding to intracellular activation is not known. Indeed, multiple mechanisms have been proposed from experimental and crystallographic data for different receptors. For example, the activation of the growth hormone receptor is proposed to involve a relative rotation of two receptor chains, while in the case of the erythropoietin receptor the chains were suggested to separate in a scissor-like mechanism. In part, this is due to the limits of resolution achievable by experimental approaches as well as a lack of appreciation for the dynamical properties of the receptor proteins and the membrane environment.This thesis focuses on the use of fully atomistic molecular dynamics simulations to investigate the mechanism of activation for the type-I cytokine receptors. In particular MD simulations are used to probe whether conformations of the receptors observed crystallographically are representative of physiological conformations. Further to this, the quality of the X-ray crystal structures is tested by recreation of the crystal lattice in MD simulations. The effect of membrane composition is investigated by comparing the behaviour of the transmembrane domain in bulk and cholesterol-enriched raft-like bilayers. Finally, receptor dimers are examined for active and inactive conformations in raft-like bilayers containing sphingomyelin. Force field parameters for the lipid sphingomyelin that were used to build raft-like bilayers were also generated and validated. The work draws into question several of the mechanistic models proposed for the type-I cytokine receptors and demonstrates the difficulty in proposing a detailed mechanism of action based on limited sets of structural data. In particular, they highlight the limitations of the use of structural data in proposing a model when only a part of the receptor is considered. Results from the simulations also suggest that the lipid composition can influence the structure and behaviour of the receptors. Taken together the work shows the importance of considering not only the ligand-binding domain of the receptor but also the restrictions imposed by the transmembrane domain and structural influences caused by the membrane when proposing a mechanism of activation for this important class of cell surface recept...

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The structure of the CD3 ζζ transmembrane dimer in POPC and raft-like lipid bilayer: A molecular dynamics study

Cited by 10 publications

References 48 publications

The cytosolic domain of T-cell receptor ζ associates with membranes in a dynamic equilibrium and deeply penetrates the bilayer

The cytosolic domain of T-cell receptor ζ associates with membranes in a dynamic equilibrium and deeply penetrates the bilayer

Transmembrane features governing Fc receptor CD16A assembly with CD16A signaling adaptor molecules

Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

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