The Lipid Modifications of Ras that Sense Membrane Environments and Induce Local Enrichment

Vogel, Alexander; Reuther, Guido; Weise, Katrin; Triola, Gemma; Nikolaus, Jörg; Tan, Kui‐Thong; Nowak, Christine; Herrmann, Andreas; Waldmann, Herbert; Winter, Roland; Huster, Daniel

doi:10.1002/anie.200903396

Cited by 68 publications

(88 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In particular, nuclear magnetic resonance (NMR) spectroscopy of the human N-Ras protein has provided a structural view of the membraneinserted lipid modifications of the protein (10)(11)(12), the conformation of the membrane-associated protein moiety (13,14), and the structural dynamics of the amino-acid residues interacting with the membrane surface (15,16). Interestingly, the Ras palmitoyl chain has been shown to adjust its length to the hydrophobic thickness of the host membrane to maximize favorable hydrophobic interactions (17). Thus, the Ras palmitoyl chain can vary its length between 8.7 Å to insert into a C12:0 DLPC (1,2-dilauroylsn-glycero-3-phosphocholine) membrane and 15.5 Å to perfectly match the C16:0 chains in a DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine)/cholesterol mixture (17).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, the Ras palmitoyl chain has been shown to adjust its length to the hydrophobic thickness of the host membrane to maximize favorable hydrophobic interactions (17). Thus, the Ras palmitoyl chain can vary its length between 8.7 Å to insert into a C12:0 DLPC (1,2-dilauroylsn-glycero-3-phosphocholine) membrane and 15.5 Å to perfectly match the C16:0 chains in a DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine)/cholesterol mixture (17). By contrast, for the myristoylated GCAP-2 protein, chain adaptation has been observed only in DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) (18) but not in POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) membranes (19), where the GCAP-2 chain is shorter than the hydrophobic thickness of the host membrane.…”

Section: Introductionmentioning

confidence: 99%

“…For nonmyristoylated Src (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), a free-energy minimum has been postulated at a distance of~3 Å between the van der Waals surfaces of the peptide and an anionic membrane (9), corresponding to one layer of water molecules (24). In the case of myristoylated Src (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), 2 H NMR spectroscopy has revealed that the acyl chain of the peptide is much more extended than the phospholipid acyl chains in a zwitterionic DMPC bilayer, such that insertion of onlỹ 11.5 carbons of the myristoyl chain suffices to match the hydrophobic thickness of the host membrane. In the presence of negatively charged lipids, the length difference between the myristoyl chain of Src and the phospholipid acyl chains is somewhat diminished (26) because the latter are slightly longer than in a zwitterionic membrane.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural Thermodynamics of myr-Src(2–19) Binding to Phospholipid Membranes

Scheidt

Klingler

Huster

et al. 2015

Biophysical Journal

Self Cite

View full text Add to dashboard Cite

Many proteins are anchored to lipid bilayer membranes through a combination of hydrophobic and electrostatic interactions. In the case of the membrane-bound nonreceptor tyrosine kinase Src from Rous sarcoma virus, these interactions are mediated by an N-terminal myristoyl chain and an adjacent cluster of six basic amino-acid residues, respectively. In contrast with the acyl modifications of other lipid-anchored proteins, the myristoyl chain of Src does not match the host lipid bilayer in terms of chain conformation and dynamics, which is attributed to a tradeoff between hydrophobic burial of the myristoyl chain and repulsion of the peptidic moiety from the phospholipid headgroup region. Here, we combine thermodynamic information obtained from isothermal titration calorimetry with structural data derived from (2)H, (13)C, and (31)P solid-state nuclear magnetic resonance spectroscopy to decipher the hydrophobic and electrostatic contributions governing the interactions of a myristoylated Src peptide with zwitterionic and anionic membranes made from lauroyl (C12:0) or myristoyl (C14:0) lipids. Although the latter are expected to enable better hydrophobic matching, the Src peptide partitions more avidly into the shorter-chain lipid analog because this does not require the myristoyl chain to stretch extensively to avoid unfavorable peptide/headgroup interactions. Moreover, we find that Coulombic and intrinsic contributions to membrane binding are not additive, because the presence of anionic lipids enhances membrane binding more strongly than would be expected on the basis of simple Coulombic attraction.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Structural Thermodynamics of myr-Src(2–19) Binding to Phospholipid Membranes

Scheidt

Klingler

Huster

et al. 2015

Biophysical Journal

Self Cite

View full text Add to dashboard Cite

show abstract

“…70 Surprisingly, in a similar system with lipidated α-helix peptides with various alkyl chain lengths, no significant adaptation of the chain length in the host membrane was observed. 65 Hence, it is unclear how generally applicable this process is for inserted lipids.…”

Section: The Role Of the Membranementioning

confidence: 94%

“…This has been observed in various studies where fluorescently labelled amphiphiles or atomic force microscopy was used. [67][68][69][70][71] Although there are no clear rules, some general trends can be observed: saturated lipid tails and sterols often associate with the Lo phase, while unsaturated lipid tails containing at least one cis double bond often associate with the Ld phase. 70,71 For example, a double cholesteryl-modified ssDNA partitioned into the Lo phase on heterogeneous giant unilamellar vesicles (GUVs) as visualized using confocal microscopy ( Figure 1.8A).…”

Section: The Role Of the Membranementioning

confidence: 99%

Supramolecular Binding of Vesicles, Viruses and Cells to Biomimetic Lipid Bilayers

Verheijden

View full text Add to dashboard Cite

Protein Association with Membrane Rafts

Veit

Thaa

2011

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Membrane rafts are very small and highly dynamic assemblies in cellular membranes enriched in cholesterol and sphingolipids. Some proteins can functionally associate with rafts: peripheral membrane proteins are incorporated into rafts depending on cues such as the presence of a glycosyl‐phosphatidylinositol (GPI) anchor or S‐acylation (palmitoylation); transmembrane proteins can partition into raft domains depending on specific features within their transmembrane domain. Raft association of membrane proteins was originally defined by their resistance to cold Triton X‐100 extraction, which is however insufficient as the sole criterion – more sophisticated methodology such as fluorescence resonance energy transfer (FRET) has to be employed to determine whether and how a given protein interacts with raft structures. Key Concepts: Membrane rafts are small, dynamic clusters within biological membranes enriched in cholesterol and sphingolipids. Rafts can be coalesced and stabilised to fulfil a biological function, for example, signal transduction or virus budding. Some proteins are capable of partitioning into raft domains. Raft‐targeting features in proteins are glycosyl‐phosphatidylinositol (GPI) anchors, S‐acylation (palmitoylation) and structural motifs in the transmembrane domain. Assessment of detergent‐resistant membranes (DRM), the original biochemical method to analyse raft association of a protein, is artefact‐prone and therefore not suitable to prove raft involvement in a biological process. More sophisticated methodology such as fluorescence resonance energy transfer (FRET) is needed to decipher raft association of a protein.

show abstract

The Lipid Modifications of Ras that Sense Membrane Environments and Induce Local Enrichment

Cited by 68 publications

References 29 publications

Structural Thermodynamics of myr-Src(2–19) Binding to Phospholipid Membranes

Structural Thermodynamics of myr-Src(2–19) Binding to Phospholipid Membranes

Supramolecular Binding of Vesicles, Viruses and Cells to Biomimetic Lipid Bilayers

Protein Association with Membrane Rafts

Contact Info

Product

Resources

About