Implications of aromatic–aromatic interactions: From protein structures to peptide models

Makwana, Kamlesh Madhusudan; Mahalakshmi, Radhakrishnan

doi:10.1002/pro.2814

Cited by 152 publications

(121 citation statements)

References 118 publications

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“…46,47 Besides, with its fused aromatic ring system Trp can undergo cation- π interactions 48 with positively charged choline groups of the lipids and detergents 49 and can also form hydrogen bonds, π -stacking, N–H··· π , and C–H··· π bonds. 50 These diverse interactions of tryptophan allow it to serve as a strong anchoring point for membrane and peripheral membrane proteins. To understand the role of Trp on phorbol ester binding in the truncated C1 domain, we generated three mutants, W22A, W22K, and W22D, in which tryptophan was replaced with a small nonpolar residue, with a positively charged residue, and with a negatively charged residue, respectively.…”

Section: Discussionmentioning

confidence: 99%

Critical Role of Trp-588 of Presynaptic Munc13-1 for Ligand Binding and Membrane Translocation

et al. 2018

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Munc13-1 is a presynaptic active-zone protein essential for neurotransmitter release and presynaptic plasticity in the brain. This multidomain scaffold protein contains a C1 domain that binds to the activator diacylglycerol/phorbol ester. Although the C1 domain bears close structural homology with the C1 domains of protein kinase C (PKC), the tryptophan residue at position 22 (588 in the full-length Munc13-1) occludes the activator binding pocket, which is not the case for PKC. To elucidate the role of this tryptophan, we generated W22A, W22K, W22D, W22Y, and W22F substitutions in the full-length Munc13-1, expressed the GFP-tagged constructs in Neuro-2a cells, and measured their membrane translocation in response to phorbol ester treatment by imaging of the live cells using confocal microscopy. The extent of membrane translocation followed the order, wild-type > W22K > W22F > W22Y > W22A > W22D. The phorbol ester binding affinity of the wild-type Munc13-1C1 domain and its mutants was phosphatidylserine (PS)-dependent following the order, wild-type > W22K > W22A ≫ W22D in both 20% and 100% PS. Phorbol ester affinity was higher for Munc13-1 than the C1 domain. While Munc13-1 translocated to the plasma membrane, the C1 domain translocated to internal membranes in response to phorbol ester. Molecular dynamics (80 ns) studies reveal that Trp-22 is relatively less flexible than the homologous Trp-22 of PKCδ and PKCθ;. Results are discussed in terms of the overall negative charge state of the Munc13-1C1 domain and its possible interaction with the PS-rich plasma membrane. This study shows that Trp-588 is an important structural element for ligand binding and membrane translocation in Munc13-1.

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Section: Discussionmentioning

confidence: 99%

Critical Role of Trp-588 of Presynaptic Munc13-1 for Ligand Binding and Membrane Translocation

et al. 2018

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“…Tryptophan is not only the most polarizable residue, but also has the capability to form a repertoire of interactions including hydrogen bonds, π-stacking, hydrophobic interactions, N—H...π, and C—H...π [7]. The diverse interaction network involving tryptophan allows this residue to serve as a strong anchoring point for membrane proteins.…”

Section: Introductionmentioning

confidence: 99%

Control of human VDAC-2 scaffold dynamics by interfacial tryptophans is position specific

Maurya

Mahalakshmi

2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Membrane proteins employ specific distribution patterns of amino acids in their tertiary structure for adaptation to their unique bilayer environment. The solvent-bilayer interface, in particular, displays the characteristic ‘aromatic belt’ that defines the transmembrane region of the protein, and satisfies the amphipathic interfacial environment. Tryptophan—the key residue of this aromatic belt—is known to influence the folding efficiency and stability of a large number of well-studied α-helical and β-barrel membrane proteins. Here, we have used functional and biophysical techniques coupled with simulations, to decipher the contribution of strategically placed four intrinsic tryptophans of the human outer mitochondrial membrane protein, voltage-dependent anion channel isoform-2 (VDAC-2). We show that tryptophans help in maintaining the structural and functional integrity of folded hVDAC-2 barrel in micellar environments. The voltage gating characteristics of hVDAC-2 are affected upon mutation of tryptophans at positions 75, 86 and 221. We observe that Trp-160 and Trp-221 play a crucial role in the folding pathway of the barrel, and once folded, Trp-221 helps stabilize the folded protein in concert with Trp-75 and Trp-160. We further demonstrate that substituting Trp-86 with phenylalanine leads to the formation of stable barrel. We find that the region comprising strand β4 (Trp-86) and β10-14 (Trp-160 and Trp-221) display slower and faster folding kinetics, respectively, providing insight into a possible directional folding of hVDAC-2 from the C-terminus to N-terminus. Our results show that residue selection in a protein during evolution is a balancing compromise between optimum stability, function, and regulating protein turnover inside the cell.

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“…The slower penetration with GN‐2 N pm 9 compared to the GN‐2 peptoid may be due to the aromatic N pm residue, which makes the hydrophobic interaction with the outer membrane lipids stronger, thus explaining the delayed penetration in the periplasmic space to reach and disturb the inner membrane. At high peptoid concentrations, self‐assembly of GN‐2 N pm 9 peptoid through aromatic‐aromatic interactions might occur, also limiting its ability to insert and penetrate the inner membrane . Remarkably, lowering the peptoid concentrations to 2× or 1× MIC, the rate of penetration into the inner membrane increased for peptides and particularly for peptoid GN‐2 N pm 9 .…”

Section: Resultsmentioning

confidence: 99%

Antibacterial mechanisms of GN‐2 derived peptides and peptoids against Escherichia coli

et al. 2019

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Escherichia coli is the main etiological agent of urinary trait infections, able to form biofilms in indwelling devices, resulting in chronic infections which are refractory to antibiotics treatment. In this study, we investigated the antimicrobial and anti‐biofilm properties exerted against E. coli ATCC 25922, by a set of peptoids and peptides modeled upon the peptide GN‐2, previously reported as a valid antimicrobial agent. The putative antimicrobials were designed to evaluate the effect of cationicity, hydrophobicity and their partitioning on the overall properties against planktonic cells and biofilms as well as on LPS binding, permeabilization of Gram‐negative bacteria membranes and hemolysis. The data demonstrated that peptides are stronger antimicrobials than the analogue peptoids which in return have superior anti‐biofilm properties. In this study, we present evidence that peptides antimicrobial activity correlates with enhanced LPS binding and hydrophobicity but is not affected by partitioning. The data demonstrated that the enhanced anti‐biofilm properties of the peptoids are associated with decreased hydrophobicity and increased penetration of the inner membrane, compared to that of their peptide counterpart, suggesting that the characteristic flexibility of peptoids or their lack of H‐bonding donors in their backbone, would play a role in their ability to penetrate bacterial membranes.

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Implications of aromatic–aromatic interactions: From protein structures to peptide models

Cited by 152 publications

References 118 publications

Critical Role of Trp-588 of Presynaptic Munc13-1 for Ligand Binding and Membrane Translocation

Critical Role of Trp-588 of Presynaptic Munc13-1 for Ligand Binding and Membrane Translocation

Control of human VDAC-2 scaffold dynamics by interfacial tryptophans is position specific

Antibacterial mechanisms of GN‐2 derived peptides and peptoids against Escherichia coli

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