Aromatic and Cation−π Interactions Enhance Helix−Helix Association in a Membrane Environment

Johnson, Rachel M.; Hecht, Karen A.; Deber, Charles M.

doi:10.1021/bi7008773

Cited by 92 publications

(72 citation statements)

References 49 publications

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“…Moreover, the presence of a phenylalanine in addition to the GXXXG motif enhances the self-association of the GpA TMD (8). Several other reports have confirmed that aromatic residues, either alone or near the GXXXG motif, can stabilize the TMD helix dimerization of membrane proteins (8,29,30 ). Therefore, we speculated that, as in the other studied receptors, phenylalanine might be involved in regulating the interaction strength of the syndecan TMDs.…”

Section: Discussionmentioning

confidence: 85%

A Unique Phenylalanine in the Transmembrane Domain Strengthens Homodimerization of the Syndecan-2 Transmembrane Domain and Functionally Regulates Syndecan-2

Kwon

Choi

Yun

et al. 2015

Journal of Biological Chemistry

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Background:The transmembrane domains of syndecan family members harbor a GXXXG motif forming non-covalently linked SDS-resistant dimers. Results: A unique phenylalanine in the syndecan-2 transmembrane domain contributes to its transmembrane homointeraction and unique functions. Conclusion: A unique phenylalanine in syndecan-2 endows its transmembrane domain with specific functions. Significance: This report provides insight into the importance of the transmembrane domain for syndecan receptor function.

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Section: Discussionmentioning

confidence: 85%

A Unique Phenylalanine in the Transmembrane Domain Strengthens Homodimerization of the Syndecan-2 Transmembrane Domain and Functionally Regulates Syndecan-2

Kwon

Choi

Yun

et al. 2015

Journal of Biological Chemistry

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“…To identify the TM residues involved in CD16A association with adaptor modules, a panel of mutants was prepared in three blocks of three mutations. Based on the documented roles of polar and aromatic residues in driving TM helix associations (17,18), we mutated these amino acid types in the CD16A TM sequence ( Fig. 2A) to alanine and evaluated the association of mutants with each signaling molecule using the IVT system described above.…”

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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“…Thus, they represent a versatile instrument for interactions between transmembrane helices. Several studies suggest that Phe, Trp and Tyr facilitate helix-helix association in transmembrane domains [82][83][84]. When placed in position i-3 of a GXXXG motif, Phe can enhance transmembrane domain interactions in model peptides derived from library screening [82].…”

Section: Aromatic Interactionsmentioning

confidence: 99%

Protein folding in membranes

Fiedler

Broecker

Keller

2010

Cell. Mol. Life Sci.

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Separation of cells and organelles by bilayer membranes is a fundamental principle of life. Cellular membranes contain a baffling variety of proteins, which fulfil vital functions as receptors and signal transducers, channels and transporters, motors and anchors. The vast majority of membrane-bound proteins contain bundles of alpha-helical transmembrane domains. Understanding how these proteins adopt their native, biologically active structures in the complex milieu of a membrane is therefore a major challenge in today's life sciences. Here, we review recent progress in the folding, unfolding and refolding of alpha-helical membrane proteins and compare the molecular interactions that stabilise proteins in lipid bilayers. We also provide a critical discussion of a detergent denaturation assay that is increasingly used to determine membrane-protein stability but is not devoid of conceptual difficulties.

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Aromatic and Cation−π Interactions Enhance Helix−Helix Association in a Membrane Environment

Cited by 92 publications

References 49 publications

A Unique Phenylalanine in the Transmembrane Domain Strengthens Homodimerization of the Syndecan-2 Transmembrane Domain and Functionally Regulates Syndecan-2

A Unique Phenylalanine in the Transmembrane Domain Strengthens Homodimerization of the Syndecan-2 Transmembrane Domain and Functionally Regulates Syndecan-2

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

Protein folding in membranes

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