From Interactions of Single Transmembrane Helices to Folding of &amp;#945;-Helical Membrane Proteins: Analyzing Transmembrane Helix-Helix Interactions in Bacteria

Schneider, Dirk; Finger, Carmen; Prodöhl, Alexander; Volkmer, Thomas

doi:10.2174/138920307779941578

Cited by 41 publications

(30 citation statements)

References 205 publications

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“…Hence, sequence motif analyses and resulting insights can support the understanding of protein dynamics. Information can be derived which may contribute to study the dynamics of mutant proteins and the effects of mutagens [23][24][25]. Additionally, as addressed in [26], the analysis of sequence motifs in proteins with similar function or structure might help to identify essential functional sites and locations which contribute to structural stability.…”

Section: Introductionmentioning

confidence: 99%

Structure Topology Prediction of Discriminative Sequence Motifs in Membrane Proteins with Domains of Unknown Functions

2013

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Motivation. Membrane proteins play essential roles in cellular processes of organisms. Photosynthesis, transport of ions and small molecules, signal transduction, and light harvesting are examples of processes which are realised by membrane proteins and contribute to a cell's specificity and functionality. The analysis of membrane proteins has shown to be an important part in the understanding of complex biological processes. Genome-wide investigations of membrane proteins have revealed a large number of short, distinct sequence motifs. Results. The in silico analysis of 32 membrane protein families with domains of unknown functions discussed in this study led to a novel approach which describes the separation of motifs by residue-specific distributions. Based on these distributions, the topology structure of the majority of motifs in hypothesised membrane proteins with unknown topology can be predicted. Conclusion. We hypothesise that short sequence motifs can be separated into structure-forming motifs on the one hand, as such motifs show high prediction accuracy in all investigated protein families. This points to their general importance in -helical membrane protein structure formation and interaction mediation. On the other hand, motifs which show high prediction accuracies only in certain families can be classified as functionally important and relevant for family-specific functional characteristics.

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Section: Introductionmentioning

confidence: 99%

Structure Topology Prediction of Discriminative Sequence Motifs in Membrane Proteins with Domains of Unknown Functions

2013

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“…The membrane-spanning segments of most of these transmembrane proteins adopt an ␣-helical conformation and can undergo highly specific, lateral interactions to form oligomeric protein complexes or properly folded multipass transmembrane proteins (2,3). These helical interactions are often essential for biological activity, but the structural basis of the vast majority of transmembrane interactions is not understood because of difficulties in obtaining high-resolution structures of transmembrane helical bundles.…”

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confidence: 99%

Compensatory Mutants of the Bovine Papillomavirus E5 Protein and the Platelet-Derived Growth Factor β Receptor Reveal a Complex Direct Transmembrane Interaction

Edwards

Xie

Bowers

et al. 2013

J Virol

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eThe 44-amino-acid E5 protein of bovine papillomavirus is a dimeric transmembrane protein that exists in a stable complex with the platelet-derived growth factor (PDGF) ␤ receptor, causing receptor activation and cell transformation. The transmembrane domain of the PDGF ␤ receptor is required for complex formation, but it is not known if the two proteins contact one another directly. Here, we studied a PDGF ␤ receptor mutant containing a leucine-to-isoleucine substitution in its transmembrane domain, which prevents complex formation with the wild-type E5 protein in mouse BaF3 cells and inhibits receptor activation by the E5 protein. We selected E5 mutants containing either a small deletion or multiple substitution mutations that restored binding to the mutant PDGF ␤ receptor, resulting in receptor activation and growth factor independence. These E5 mutants displayed lower activity with PDGF ␤ receptor mutants containing other transmembrane substitutions in the vicinity of the original mutation, and one of them cooperated with a receptor mutant containing a distal mutation in the juxtamembrane domain. These results provide strong genetic evidence that the transmembrane domains of the E5 protein and the PDGF ␤ receptor contact one another directly. They also demonstrate that different mutations in the E5 protein allow it to tolerate the same mutation in the PDGF ␤ receptor transmembrane domain and that a mutation in the E5 protein can allow it to tolerate different mutations in the PDGF ␤ receptor. Thus, the rules governing direct interactions between transmembrane helices are complex and not restricted to local interactions. Proteins that span cellular membranes are thought to comprise up to 30% of the proteome (1). The membrane-spanning segments of most of these transmembrane proteins adopt an ␣-helical conformation and can undergo highly specific, lateral interactions to form oligomeric protein complexes or properly folded multipass transmembrane proteins (2, 3). These helical interactions are often essential for biological activity, but the structural basis of the vast majority of transmembrane interactions is not understood because of difficulties in obtaining high-resolution structures of transmembrane helical bundles. Mutational analysis showed that homodimeric helix-helix interactions can be determined by highly specific interactions between amino acid side chains (4). Formation of heteromeric transmembrane complexes can be mediated by interactions between hydrophilic amino acid side chains (5-7), but the structural basis for the specificity of heteromeric transmembrane interactions has not been studied in detail. In our laboratory, we have developed genetic methods to analyze heteromeric transmembrane interactions in mammalian cells and showed that artificial transmembrane proteins can undergo specific functional interactions with native transmembrane proteins (8-12).The 44-amino-acid E5 oncoprotein of bovine papillomavirus type 1 (BPV) is essentially an isolated transmembrane domain that forms a homodime...

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“…The approach represents a modification on earlier methods to monitor homomeric and heteromeric TM helix-helix association (13)(14)(15)(16)(17)(18) that is sufficiently specific to allow measurement of fine changes in heterodimeric TM helix-helix association. We then employed these methods, in conjunction with structural bioinformatics, to identify a unique interaction motif that is conserved between the TM helices of the integrins α IIb β 3 , α ν β 3 , α 2 β 1 , and α 5 β 1 .…”

mentioning

confidence: 99%

Consensus motif for integrin transmembrane helix association

Berger

Kulp²,

Span³

et al. 2009

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

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Interactions between transmembrane (TM) helices play an important role in the regulation of diverse biological functions. For example, the TM helices of integrins are believed to interact heteromerically in the resting state; disruption of this interaction results in integrin activation and cellular adhesion. However, it has been difficult to demonstrate the specificity and affinity of the interaction between integrin TM helices and to relate them to the activation process. To examine integrin TM helix associations, we developed a bacterial reporter system and used it to define the sequence motif required for helix-helix interactions in the β 1 and β 3 integrin subfamilies. The helices interact in a novel three-dimensional motif, the "reciprocating large-small motif" that is also observed in the crystal structures of unrelated proteins. Modest but specific stabilization of helix associations is realized via packing of complementary small and large groups on neighboring helices. Mutations destabilizing this motif activate native, fulllength integrins. Thus, this highly conserved dissociable motif plays a vital and widespread role as an on-off switch that can integrate with other control elements during integrin activation.interaction motif | transmembrane domain

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From Interactions of Single Transmembrane Helices to Folding of α-Helical Membrane Proteins: Analyzing Transmembrane Helix-Helix Interactions in Bacteria

Cited by 41 publications

References 205 publications

Structure Topology Prediction of Discriminative Sequence Motifs in Membrane Proteins with Domains of Unknown Functions

Structure Topology Prediction of Discriminative Sequence Motifs in Membrane Proteins with Domains of Unknown Functions

Compensatory Mutants of the Bovine Papillomavirus E5 Protein and the Platelet-Derived Growth Factor β Receptor Reveal a Complex Direct Transmembrane Interaction

Consensus motif for integrin transmembrane helix association

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