Polar/Ionizable Residues in Transmembrane Segments: Effects on Helix-Helix Packing

Bañó‐Polo, Manuel; Baeza-Delgado, Carlos; Orzáez, Mar; Martí‐Renom, Marc A.; Abad, Concepción; Mingarro, Ismael

doi:10.1371/journal.pone.0044263

Cited by 28 publications

(33 citation statements)

References 44 publications

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“…Thus, multiple contacts are important for the pilin-PilS interaction. Rare charged residues in TM segments are typically buried within multi-TM proteins or involved in protein-protein interactions (48,49). PilA E5K or PilS R24E substitutions disrupted PilA-PilS interactions and dysregulated PilA expression, but the PilA E5K and PilS R24E charged-swapped pair failed to interact (Fig.…”

Section: Discussionmentioning

confidence: 99%

Type IV pilins regulate their own expression via direct intramembrane interactions with the sensor kinase PilS

Kilmury

Burrows

2016

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

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Type IV pili are important virulence factors for many pathogens, including Pseudomonas aeruginosa. Transcription of the major pilin gene—pilA—is controlled by the PilS-PilR two-component system in response to unknown signals. The absence of a periplasmic sensing domain suggested that PilS may sense an intramembrane signal, possibly PilA. We suggest that direct interactions between PilA and PilS in the inner membrane reduce pilA transcription when PilA levels are high. Overexpression in trans of PilA proteins with diverse and/or truncated C termini decreased native pilA transcription, suggesting that the highly conserved N terminus of PilA was the regulatory signal. Point mutations in PilA or PilS that disrupted their interaction prevented autoregulation of pilA transcription. A subset of PilA point mutants retained the ability to interact with PilS but could no longer decrease pilA transcription, suggesting that interaction between the pilin and sensor kinase is necessary but not sufficient for pilA autoregulation. Furthermore, PilS’s phosphatase motif was required for the autoregulation of pilA transcription, suggesting that under conditions where PilA is abundant, the PilA–PilS interaction promotes PilR dephosphorylation and thus down-regulation of further pilA transcription. These data reveal a clever bacterial inventory control strategy in which the major subunit of an important P. aeruginosa virulence factor controls its own expression.

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Section: Discussionmentioning

confidence: 99%

Type IV pilins regulate their own expression via direct intramembrane interactions with the sensor kinase PilS

Kilmury

Burrows

2016

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

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“…30 Although hydrophobic interactions between TM segments are more abundant, hydrogen bonding or salt-bridge formation between membrane-spanning charged residues is essential to drive membrane protein folding while, at the same time, reducing the unfavorable energetics of inserting charged residues into the membrane. 31 Hence, interactions between polar residues in adjacent TM segments have been shown to favor membrane insertion. [32][33][34] PV 2B comprises two TM segments harboring conserved charged residues.…”

Section: Discussionmentioning

confidence: 99%

Charge Pair Interactions in Transmembrane Helices and Turn Propensity of the Connecting Sequence Promote Helical Hairpin Insertion

Bañó‐Polo

Martínez-Gil

Wallner

et al. 2013

Journal of Molecular Biology

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α-Helical hairpins, consisting of a pair of closely spaced transmembrane (TM) helices that are connected by a short interfacial turn, are the simplest structural motifs found in multi-spanning membrane proteins. In naturally occurring hairpins, the presence of polar residues is common and predicted to complicate membrane insertion. We postulate that the pre-packing process offsets any energetic cost of allocating polar and charged residues within the hydrophobic environment of biological membranes. Consistent with this idea, we provide here experimental evidence demonstrating that helical hairpin insertion into biological membranes can be driven by electrostatic interactions between closely separated, poorly hydrophobic sequences. Additionally, we observe that the integral hairpin can be stabilized by a short loop heavily populated by turn-promoting residues. We conclude that the combined effect of TM-TM electrostatic interactions and tight turns plays an important role in generating the functional architecture of membrane proteins and propose that helical hairpin motifs can be acquired within the context of the Sec61 translocon at the early stages of membrane protein biosynthesis. Taken together, these data further underline the potential complexities involved in accurately predicting TM domains from primary structures.

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“…Nonetheless, the presence of charged amino acid residues (lysine, arginine) in the CP sequence suggests that incorporation of the CP into the membrane might be energetically unfavorable. However, Bano-Polo et al [51] showed that for the GpA trans-membrane sequence, replacement of nonpolar residues with polar residues (including lysine and arginine) did not hinder dimerization of the protein and its insertion into hydrophobic environment when these residues pointed to the lipid facing interface. However, point mutations at residues located at the helix-helix interface abolished dimerization.…”

Section: Discussionmentioning

confidence: 99%

The Topology, in Model Membranes, of the Core Peptide Derived from the T‐Cell Receptor Transmembrane Domain

et al. 2013

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The T-cell receptor-CD3 complex (TCR-CD3) serves a critical role in protecting organisms from infectious agents. The TCR is a heterodimer composed of α- and β-chains, which are responsible for antigen recognition. Within the transmembrane domain of the α-subunit, a region has been identified to be crucial for the assembly and function of the TCR. This region, termed core peptide (CP), consists of nine amino acids (GLRILLLKV), two of which are charged (lysine and arginine) and are crucial for the interaction with CD3. Earlier studies have shown that a synthetic peptide corresponding to the CP sequence can suppress the immune response in animal models of T-cell-mediated inflammation, by disrupting proper assembly of the TCR. As a step towards the understanding of the source of the CP activity, we focused on CP in egg phosphatidylcholine/cholesterol (9:1, mol/mol) model membranes and determined its secondary structure, oligomerization state, and orientation with respect to the membrane. To achieve this goal, 15-residue segments of TCRα, containing the CP, were synthesized and spin-labeled at different locations with a nitroxide derivative. Electron spin-echo envelope modulation spectroscopy was used to probe the position and orientation of the peptides within the membrane, and double electron-electron resonance measurements were used to probe its conformation and oligomerization state. We found that the peptide is predominantly helical in a membrane environment and tends to form oligomers (mostly dimers) that are parallel to the membrane plane.

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Polar/Ionizable Residues in Transmembrane Segments: Effects on Helix-Helix Packing

Cited by 28 publications

References 44 publications

Type IV pilins regulate their own expression via direct intramembrane interactions with the sensor kinase PilS

Type IV pilins regulate their own expression via direct intramembrane interactions with the sensor kinase PilS

Charge Pair Interactions in Transmembrane Helices and Turn Propensity of the Connecting Sequence Promote Helical Hairpin Insertion

The Topology, in Model Membranes, of the Core Peptide Derived from the T‐Cell Receptor Transmembrane Domain

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