Folding and Stability of α-Helical Integral Membrane Proteins

MacKenzie, Kevin R.

doi:10.1021/cr0404388

Cited by 195 publications

(126 citation statements)

References 664 publications

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“…More generally, information from such a systematic analysis may offer insight into the nonrandom statistics of residueresidue correlation in β sheets and in α as well as 3 10 helices [67]. As suggested above, extension of the present approach should also be relevant to understanding secondary structure formation in transmembrane proteins, which can have predominantly α-helical [68,69] or β-barrel [70,71] structures. It would be interesting to explore the role of dbrelated and steric constraints in the conformational transitions between water-soluble and membrane-bound forms of these proteins.…”

Section: Discussionmentioning

confidence: 83%

Hydrophobic interactions in the formation of secondary structures in small peptides

2011

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Effects of the attractive and repulsive parts of hydrophobic interactions on α helices and β sheets in small peptides are investigated using a simple atomic potential. Typically, a physical spatial range of attraction tends to favor β sheets, but α helices would be favored if the attractive range were more extended. We also found that desolvation barriers favor β sheets in collapsed conformations of polyalanine, polyvaline, polyleucine, and three fragments of amyloid peptides tested in this study. Our results provide insight into the multifaceted role of hydrophobicity in secondary structure formation, including the α to β transitions in certain amyloid peptides.

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Section: Discussionmentioning

confidence: 83%

Hydrophobic interactions in the formation of secondary structures in small peptides

2011

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“…Although TMD homodimerization has been implicated in syndecan function, the interaction strengths of the syndecan paralog TMDs have not been determined relative to one another, or by comparison to other TMDs known to self-associate (23). Here, we measure the association tendencies of the syndecan TMDs in both membranes and detergents, independent of the ectodomain and endodomains found in the native proteins.…”

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confidence: 99%

Transmembrane domains of the syndecan family of growth factor coreceptors display a hierarchy of homotypic and heterotypic interactions

Dews

MacKenzie

2007

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

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105

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The single-pass transmembrane domains (TMDs) of the syndecan family of cell surface adhesion molecules have been implicated in functional protein-protein interactions. Although each paralog contains a conserved GxxxG dimerization motif, we show here that the syndecan-1 TMD dimerizes weakly, the syndecan-3 and syndecan-4 TMDs each dimerize strongly, and the syndecan-2 TMD dimerizes very strongly. These markedly different levels of selfassociation suggest that paralog TMDs play different roles in directing functional interactions of each full-length syndecan family member. We further show that each syndecan TMD forms detergent-resistant heteromeric complexes with other paralogs, and that these interactions exhibit selectivity. Although heteromeric interactions among full-length syndecan paralogs have not been reported, we argue that the distinct hierarchy of proteinprotein interactions mediated by the syndecan TMDs may give rise to considerable complexity in syndecan function. The demonstration that TMD homodimerization and heterodimerization can be mediated by GxxxG motifs and modulated by sequence context has implications for the signaling mechanisms of other cell surface receptors, including the integrins and the erbB family.homodimerization ͉ heterodimerization ͉ selectivity S yndecans are cell surface receptors that participate in cellcell and cell-matrix interactions critical to animal development. In mammals, where four syndecan paralogs exist (1-5), syndecan expression is tissue-specific and developmentally regulated, with most cells expressing one or more syndecans (6, 7). Syndecan-1 plays roles in early development (8-10) and wound healing (11), and syndecan-2 participates in neuronal dendritic spine morphogenesis (12), angiogenic sprouting (13), and Xenopus left/right axis formation (14). Syndecan-3 is involved in skeletogenesis (15), and syndecan-4 participates in the formation of integrin-containing focal adhesions (16). Although our knowledge of the mechanisms underlying syndecan biology is still sparse, it is already clear that understanding syndecan function has implications for treatment of cancer, wound healing, and viral and bacterial pathogenesis (reviewed in ref. 17).Each syndecan contains an ectodomain, a transmembrane domain (TMD), and a short, C-terminal cytoplasmic domain. Syndecan family members interact with a wide array of partners: the divergent heparan sulfate-modified ectodomains bind matrix proteins and growth factors, and the cytosolic domains bind cytoskeletal proteins and PDZ-domain proteins through the C1 and C2 regions (reviewed in refs. 18 and 19). Syndecan TMDs are also thought to make functional interactions: some functions of syndecan-2 and syndecan-4 depend on self-association through their TMDs (20), and the TMD of syndecan-1 makes interactions that lead to the initial spreading response of Raji cells (21). The first evidence of TMD involvement in syndecan protein-protein interactions was the attribution of detergentresistant noncovalent oligomerization of the syndecan-3 ...

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“…The GpA TM helix provides an excellent prototype for the study of TM helix association, a key event in the folding of membrane proteins (18). The dimer also is an appropriate model for these investigations, because it is stable in a variety of micelles, including SDS (19), and a solution NMR structure is available (20). There are two Gly residues at the dimer interface that allow an intimate contact of the main chain, a feature frequently observed in TM helical interfaces (21,22).…”

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confidence: 99%

Amide vibrations are delocalized across the hydrophobic interface of a transmembrane helix dimer

Fang

Senes

Cristian

et al. 2006

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

129

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The tertiary interactions between amide-I vibrators on the separate helices of transmembrane helix dimers were probed by ultrafast 2D vibrational photon echo spectroscopy. The 2D IR approach proves to be a useful structural method for the study of membrane-bound structures. The 27-residue human erythrocyte protein Glycophorin A transmembrane peptide sequence: KKITLIIFG79VMAGVIGTILLISWG94IKK was labeled at G79 and G94 with 13 tertiary interaction ͉ vibrational spectra ͉ multidimensional spectroscopy T wo-dimensional IR spectroscopy (1-6) is a promising new method with which to probe structures and their motions in complex systems. Recent applications of this method to biologically related molecules have yielded novel structural and dynamical results not readily obtainable by other methods for small peptides (7,8), soluble helices (9, 10), membrane-bound helices (11), lipids (12), ␤-sheets (13, 14), and model secondary structures (15, 16). The 2D IR approach is one that can be immediately applicable to a wide variety of sample types ranging from solutions to solids, including aqueous and lipid environments. The method exposes interactions between spatially nearby vibrational modes by converting three pulse photon echo signals into 2D spectral maps in the IR, analogous to 2D NMR spectra.The amide-I vibrational bands of polypeptides are highly degenerate because, for each residue, their frequencies are approximately the same and the interactions among them are not strong enough to separately display them as individual, assignable transitions. The combination of multiple isotope selection and 2D IR spectroscopy that spreads the transitions into two dimensions proves to be a useful strategy that can simplify and expose the underlying transitions of the diffuse amide bands and allow their features to be characterized at a residue level. For example the 2D IR spectrum of a water-soluble helix selectively substituted with 13 CA 16 O and 13 CA 18 O provided characteristics of pairs of coupled residues and the visualization of the sequence dependence of the structural dynamics (17). This paper introduces a comparable approach to investigate tertiary interactions between vibrational modes in Glycophorin A (GpA), a transmembrane (TM) dimer of interacting helices (Fig. 1). The GpA TM helix provides an excellent prototype for the study of TM helix association, a key event in the folding of membrane proteins (18). The dimer also is an appropriate model for these investigations, because it is stable in a variety of micelles, including SDS (19), and a solution NMR structure is available (20). There are two Gly residues at the dimer interface that allow an intimate contact of the main chain, a feature frequently observed in TM helical interfaces (21,22). Because vibrational coupling is sensitive to distance, the proximity of the backbones is advantageous. GpA also was selected because verification of the applicability of the 2D IR method to membrane protein aggregates is of great interest and because there is a chronic paucity o...

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Folding and Stability of α-Helical Integral Membrane Proteins

Cited by 195 publications

References 664 publications

Hydrophobic interactions in the formation of secondary structures in small peptides

Hydrophobic interactions in the formation of secondary structures in small peptides

Transmembrane domains of the syndecan family of growth factor coreceptors display a hierarchy of homotypic and heterotypic interactions

Amide vibrations are delocalized across the hydrophobic interface of a transmembrane helix dimer

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