PREDDIMER: a web server for prediction of transmembrane helical dimers

Polyansky, Anton A.; Chugunov, Anton O.; Volynsky, Pavel E.; Крылов, Н. А.; Nolde, Dmitry E.; Efremov, Roman G.

doi:10.1093/bioinformatics/btt645

Cited by 77 publications

(93 citation statements)

References 9 publications

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“…7A)), suggesting that A1-A5 protrude from the N-terminal side, whereas T1-T5 protrude from the C-terminal side of the transmembrane helix. This conclusion was further verified by modeling the structures of various TMD mutations using PREDDIMER (47). No large differences in the structure or helix-helix orientation were observed between the wild type, A5, and T4 mutants or IFNAR2 homodimer for the top two scoring TMD structures (Fig.…”

Section: Sequence Conservation Of Tmds and Their Surroundings-supporting

confidence: 58%

“…It was shown for other transmembrane helices that the experimentally determined conformation is among the top-scoring models for a given dimer (47). The F SCORE values of the three highest ranking TMDs for the wild-type receptors were 1.1, 0.96, and 0.92, respectively, much below the predicted threshold for TMD interactions in PRED-DIMER (47), suggesting that the TMDs of IFNAR1 and IFNAR2 do not interact. Interestingly, the only TMD with higher F SCORE values is for the IFNAR2 homodimer (2.4), which we have experimentally shown not to interact (Fig.…”

Section: Sequence Conservation Of Tmds and Their Surroundings-mentioning

confidence: 99%

“…(46) of wild-type, A5, and T4 insertions (of five and four Ala residues) and Lys-458 and Val-459 to Ala mutations. B, modeling the structures of IFNAR1-IFNAR2 TMD arrangements using PREDDIMER (47). As input we used the predicted TMD regions, spanning from IW to AA for IFNAR1 (21 amino acids) and from IG to TL for IFNAR2 (21 amino acids, see C and D in red).…”

Section: Sequence Conservation Of Tmds and Their Surroundings-mentioning

confidence: 99%

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Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Sharma

Longjam

Schreiber

2016

Journal of Biological Chemistry

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Type I interferons serve as the first line of defense against pathogen invasion. Binding of IFNs to its receptors, IFNAR1 and IFNAR2, is leading to activation of the IFN response. To determine whether structural perturbations observed during binding are propagated to the cytoplasmic domain, multiple mutations were introduced into the transmembrane helix and its surroundings. Insertion of one to five alanine residues near either the N or C terminus of the transmembrane domain (TMD) likely promotes a rotation of 100°and a translation of 1.5 Å per added residue. Surprisingly, the added alanines had little effect on the binding affinity of IFN to the cell surface receptors, STAT phosphorylation, or gene induction. Similarly, substitution of the juxtamembrane residues of the TMD with alanines, or replacement of the TMD of IFNAR1 with that of IFNAR2, did not affect IFN binding or activity. Finally, only the addition of 10 serine residues (but not 2 or 4) between the extracellular domain of IFNAR1 and the TMD had some effect on signaling. Bioinformatic analysis shows a correlation between high sequence conservation of TMDs of cytokine receptors and the ability to transmit structural signals. Sequence conservation near the TMD of IFNAR1 is low, suggesting limited functional importance for this region. Our results suggest that IFN binding to the extracellular domains of IFNAR1 and IFNAR2 promotes proximity between the intracellular domains and that differential signaling is a function of duration of activation and affinity of binding rather than specific conformational changes transmitted from the outside to the inside of the cell.Type I interferons (IFNs) orchestrate the antiviral innate immunity in vertebrates. They consist of 16 members in humans as follows: 12 different IFN␣ subtypes, as well as IFN␤, IFN, IFN⑀, and IFN. They are clustered on the short arm of chromosome 9. All type I interferons elicit their innate and adaptive immune responses after binding to the receptor and forming the IFNAR1-IFN-IFNAR2 ternary complex (1, 2), the formation of which is essential for signaling. Both IFNAR1 and IFNAR2 belong to the class II helical cytokine receptors with four fibronectin type III-like subdomains for IFNAR1 and two subdomains for IFNAR2. The extracellular domains are followed by a single helix of 21 amino acids spanning the membrane, which in turn is connected to mostly natively unstructured intracellular domains and their associated effectors (Fig. 1A) (3). Cells lacking one of the receptors lack normal IFN signaling (4, 5). Structurally different members of type I IFNs bind to the same cell surface receptor but mediate differential responses that result from differences in binding affinities, concentration of IFN, and duration of activation (5-13). Differential signaling is realized through robust (antiviral) versus tunable (antiproliferative and immunomodulatory) gene induction leading to different phenotypic outcomes (14,15). Receptor dimerization drives the activation of cytosolic associated Janus family kina...

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Section: Sequence Conservation Of Tmds and Their Surroundings-supporting

confidence: 58%

Section: Sequence Conservation Of Tmds and Their Surroundings-mentioning

confidence: 99%

Section: Sequence Conservation Of Tmds and Their Surroundings-mentioning

confidence: 99%

See 1 more Smart Citation

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Sharma

Longjam

Schreiber

2016

Journal of Biological Chemistry

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“…Molecular Modeling of the TMD Dimer-Molecular modeling of the self-association of EphA2 TMD (residues 532-562) was performed with the PREDDIMER program (38). The set of five dimer structures was predicted with the F SCOR values var-ied from 1.593-2.426.…”

Section: Methodsmentioning

confidence: 99%

Point Mutations in Dimerization Motifs of the Transmembrane Domain Stabilize Active or Inactive State of the EphA2 Receptor Tyrosine Kinase

Шаронов

Bocharov

Kolosov

et al. 2014

Journal of Biological Chemistry

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Background: Isolated Eph transmembrane domains (TMD) dimerize in membrane mimetics, but the functional significance of these interactions is unclear. Results: Mutations introduced into the alternative dimerization motifs of the EphA2 TMD induced an opposite effect on receptor activity. Conclusion: Alternative TMD interactions promote either the active or inactive EphA2 conformation. Significance: The involvement of TMD interactions in Eph receptor activity is discovered.The EphA2 receptor tyrosine kinase plays a central role in the regulation of cell adhesion and guidance in many human tissues. The activation of EphA2 occurs after proper dimerization/ oligomerization in the plasma membrane, which occurs with the participation of extracellular and cytoplasmic domains. Our study revealed that the isolated transmembrane domain (TMD) of EphA2 embedded into the lipid bicelle dimerized via the heptad repeat motif L 535 X 3 G 539 X 2 A 542 X 3 V 546 X 2 L 549 rather than through the alternative glycine zipper motif A 536 X 3 G 540 X 3 G 544(typical for TMD dimerization in many proteins). To evaluate the significance of TMD interactions for full-length EphA2, we substituted key residues in the heptad repeat motif (HR variant: G539I, A542I, G553I) or in the glycine zipper motif (GZ variant: G540I, G544I) and expressed YFP-tagged EphA2 (WT, HR, and GZ variants) in HEK293T cells. Confocal microscopy revealed a similar distribution of all EphA2-YFP variants in cells. The expression of EphA2-YFP variants and their kinase activity (phosphorylation of Tyr 588 and/or Tyr 594) and ephrin-A3 binding were analyzed with flow cytometry on a single cell basis. Activation of any EphA2 variant is found to occur even without ephrin stimulation when the EphA2 content in cells is sufficiently high. Ephrin-A3 binding is not affected in mutant variants. Mutations in the TMD have a significant effect on EphA2 activity. Both ligand-dependent and ligand-independent activities are enhanced for the HR variant and reduced for the GZ variant compared with the WT. These findings allow us to suggest TMD dimerization switching between the heptad repeat and glycine zipper motifs, corresponding to inactive and active receptor states, respectively, as a mechanism underlying EphA2 signal transduction.Receptor tyrosine kinases of the Eph family and their ephrin ligands are key regulators of cell-cell and cell-matrix adhesion, coordinating cell migration and positioning in various adult and embryonic tissues of human organisms (1, 2). The EphA2 receptor, a representative of the human 14-member Eph family, controls such diverse processes as capillary stabilization by pericytes (3), keratinocyte movement out of the basal layer (2), blastocyst entry into the endometrial layer (4), and cardiac stem cell mobilization from the niche (5). Activation of EphA2 leads to cell detachment (mobilization), loss of intercellular contacts (an increase in cell layer permeability), or cell repulsion (guidance).A classical model of EphA2 activation assumes the binding of a li...

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“…Although such methods are computationally expensive, recently some simplified approaches have been developed that are compatible with the screening of a large number of TM helices. For example, the PREDDIMER algorithm 140,141 has been validated against several helix pairs with available NMR structures 139,141 and is available via a web server (http://model.nmr.ru/preddimer/). The "Cα Transmembrane" (CATM) method developed by the Senes lab initially screens pairs of TM helices for local geometry that allows CαH···OC hydrogen bonding, using precalculated sequence-based rules.…”

Section: Biochemistrymentioning

confidence: 99%

Role of GxxxG Motifs in Transmembrane Domain Interactions

2015

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Transmembrane (TM) helices of integral membrane proteins can facilitate strong and specific noncovalent protein-protein interactions. Mutagenesis and structural analyses have revealed numerous examples in which the interaction between TM helices of single-pass membrane proteins is dependent on a GxxxG or (small)xxx(small) motif. It is therefore tempting to use the presence of these simple motifs as an indicator of TM helix interactions. In this Current Topic review, we point out that these motifs are quite common, with more than 50% of single-pass TM domains containing a (small)xxx(small) motif. However, the actual interaction strength of motif-containing helices depends strongly on sequence context and membrane properties. In addition, recent studies have revealed several GxxxG-containing TM domains that interact via alternative interfaces involving hydrophobic, polar, aromatic, or even ionizable residues that do not form recognizable motifs. In multipass membrane proteins, GxxxG motifs can be important for protein folding, and not just oligomerization. Our current knowledge thus suggests that the presence of a GxxxG motif alone is a weak predictor of protein dimerization in the membrane.

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PREDDIMER: a web server for prediction of transmembrane helical dimers

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 77 publications

References 9 publications

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Point Mutations in Dimerization Motifs of the Transmembrane Domain Stabilize Active or Inactive State of the EphA2 Receptor Tyrosine Kinase

Role of GxxxG Motifs in Transmembrane Domain Interactions

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