Helix-packing motifs in membrane proteins

Walters, Robin F.S.; DeGrado, William F.

doi:10.1073/pnas.0605878103

Cited by 258 publications

(296 citation statements)

References 32 publications

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“…The formation of P321 by this protein may be kinetically and entropically more facile than that of P6. Furthermore, the antiparallel packing involves an extended right-handed "glycine zipper" motif (GX 3 GX 3 A) (44), which is similar to the GX 3 G motif but is found in both parallel and antiparallel orientations (45,46). Sequence-Structure Energy Landscape.…”

Section: Resultsmentioning

confidence: 99%

Computational design of a protein crystal

Lanci

MacDermaid

Kang

et al. 2012

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

158

165

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Protein crystals have catalytic and materials applications and are central to efforts in structural biology and therapeutic development. Designing predetermined crystal structures can be subtle given the complexity of proteins and the noncovalent interactions that govern crystallization. De novo protein design provides an approach to engineer highly complex nanoscale molecular structures, and often the positions of atoms can be programmed with sub-Å precision. Herein, a computational approach is presented for the design of proteins that self-assemble in three dimensions to yield macroscopic crystals. A three-helix coiled-coil protein is designed de novo to form a polar, layered, three-dimensional crystal having the P6 space group, which has a "honeycomb-like" structure and hexameric channels that span the crystal. The approach involves: (i) creating an ensemble of crystalline structures consistent with the targeted symmetry; (ii) characterizing this ensemble to identify "designable" structures from minima in the sequencestructure energy landscape and designing sequences for these structures; (iii) experimentally characterizing candidate proteins. A 2.1 Å resolution X-ray crystal structure of one such designed protein exhibits sub-Å agreement [backbone root mean square deviation (rmsd)] with the computational model of the crystal. This approach to crystal design has potential applications to the de novo design of nanostructured materials and to the modification of natural proteins to facilitate X-ray crystallographic analysis.M olecular design provides powerful tools for exploring how molecular properties dictate macroscopic structure and function. One of the most precise forms of self-organization, crystallization achieves orientation and symmetry across many length scales and can be leveraged to engineer materials with well-defined molecular order (1). In addition to their central role in structure determination, molecular crystals have many applications, including nanoparticle templating (2, 3), nonlinear optical devices (4), molecular scaffolding (5), and porous frameworks (6). A predictive understanding of how to achieve self-assembled macroscale structure and desired properties remains challenging, however, particularly when large, conformationally flexible molecules are employed.Small synthetic molecules have been designed that display complementary functional groups in a manner consistent with a chosen crystal structure. Intermolecular contacts are often patterned using strong, directional interactions (e.g., hydrogen bonding, metalcoordination, and electrostatic interactions) (7). The constituent molecules, however, are typically small and synthetic, thus limiting size, shape, and functionality. Hence, simultaneously achieving functional properties and the presentation of complementary intermolecular interactions that confer a targeted crystal structure can be difficult. Commonly, weak intermolecular forces stabilize crystalline ordering, and as a result, quantitative, predictive approaches to crystal de...

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Section: Resultsmentioning

confidence: 99%

Computational design of a protein crystal

Lanci

MacDermaid

Kang

et al. 2012

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

158

165

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“…Within a family, the FPs of viral fusion proteins have highly conserved sequence motifs, such as heptad repeats of small residues, that are similar to those important for association of other oligomeric TM helical bundles (45,47,48) (Table S1), suggesting that TM helix-helix association might be relevant to fusion. In this regard, it is interesting to compare the avidity of homo- and heterooligomer formation for the C-term-TM and FP of the PIV5 F protein.…”

Section: Discussionmentioning

confidence: 99%

“…Also, replacing C-term-TM helices of fusogenic proteins with lipid anchors results in a loss of fusion (39)(40)(41)(42) and, surprisingly, FP sequences often show greater conservation than might be expected from the functional requirements for membrane binding (43). Moreover, the very strong conservation of polar and small residues at regularly spaced intervals as found in GXXXG (44)(45)(46), glycine zippers (47), and GAS (glycine-alanine-serine) motifs (48) (Table S1), is intriguing. These patterns are known to stabilize TM helix association and also figure in the helix-helix packing of proteins that undergo large-scale conformational changes in response to lipidic environment, such as in mechanosensitive (MS) channels (49).…”

mentioning

confidence: 97%

Transmembrane orientation and possible role of the fusogenic peptide from parainfluenza virus 5 (PIV5) in promoting fusion

Donald¹,

Zhang

Fiorin

et al. 2011

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

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Membrane fusion is required for diverse biological functions ranging from viral infection to neurotransmitter release. Fusogenic proteins increase the intrinsically slow rate of fusion by coupling energetically downhill conformational changes of the protein to kinetically unfavorable fusion of the membrane-phospholipid bilayers. Class I viral fusogenic proteins have an N-terminal hydrophobic fusion peptide (FP) domain, important for interaction with the target membrane, plus a C-terminal transmembrane (C-term-TM) helical membrane anchor. The role of the water-soluble regions of fusogenic proteins has been extensively studied, but the contributions of the membrane-interacting FP and C-term-TM peptides are less well characterized. Typically, FPs are thought to bind to membranes at an angle that allows helix penetration but not traversal of the lipid bilayer. Here, we show that the FP from the paramyxovirus parainfluenza virus 5 fusogenic protein, F, forms an N-terminal TM helix, which self-associates into a hexameric bundle. This FP also interacts strongly with the C-term-TM helix. Thus, the fusogenic F protein resembles SNARE proteins involved in vesicle fusion by having water-soluble coiled coils that zipper during fusion and TM helices in both membranes. By analogy to mechanosensitive channels, the force associated with zippering of the water-soluble coiled-coil domain is expected to lead to tilting of the FP helices, promoting interaction with the C-term-TM helices. The energetically unfavorable dehydration of lipid headgroups of opposing bilayers is compensated by thermodynamically favorable interactions between the FP and C-term-TM helices as the coiled coils zipper into the membrane phase, leading to a pore lined by both lipid and protein.T he basic mechanisms of viral membrane fusion have been studied extensively, but major gaps remain in our understanding of the relative roles of lipidic intermediates and viral fusogenic proteins in lowering the energy barrier for the overall process (1-4). The most common mechanistic hypothesis concerning enveloped viral fusion is that fusogenic proteins primarily serve to bring the target cell and viral membranes into proximity. Fusion occurs in a multistep process, in which the virus first binds to a specific receptor; this event and/or other environmental cues then cause a conformational change in the protein, leading to a metastable state with an exposed hydrophobic fusion peptide (FP) that binds to the target membrane. Once engaged with the bilayer, a second energetically favorable conformational change in the fusogenic protein then exerts a force pulling the FP toward the viral membrane, in effect reeling the host and viral membranes together.The conformational changes involved in the water-soluble portions of viral fusogenic proteins have been largely elucidated, but the roles of the membrane-binding FP and the C-terminal transmembrane (C-term-TM) anchor are less clear. After the crystal structure of the prefusogenic form of influenza hemagglutinin (HA) was solved...

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“…It includes unusually large quantity of aromatic residues -6 Phe and Trp and a cluster of relatively polar residues (Asn 709 Thr 710 Ser 711 ) deep inside the membrane. It is well-known that highly polar residues in TM helices can drive their association [41,42], and slightly polar residues, such as Gly, Ser, Thr and Ala can mediate the TM helix-helix interactions if they are put together in special motifs, such as GxxxG or ''heptad-repeat'' [43,44]. Aromatic sidechains also bear partial charges and can engage in electrostatic interactions with other aromatic residues or polar sidechains, thus stabilizing the dimerization/oligomerization of TM segments [45].…”

Section: Discussionmentioning

confidence: 99%

Toll‐like receptor 3 transmembrane domain is able to perform various homotypic interactions: An NMR structural study

2014

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Edited by Christian Griesinger Keyword:Toll-like receptor Transmembrane domain Spatial structure Dimerization Free energy a b s t r a c t Toll-like receptors (TLRs) take part in both the innate and adaptive immune systems. The role of the transmembrane domain in TLR signaling is still elusive, while its importance for the TLR activation was clearly demonstrated. In the present study the ability of the TLR3 transmembrane domain to form dimers and trimers in detergent micelles was shown by solution NMR spectroscopy. Spatial structures and free energy magnitudes were determined for the TLR3 transmembrane domain in dimeric and trimeric states, and two possible surfaces that may be used for the helix-helix interaction by the full-length TLR3 were revealed. Structured summary of protein interactions:TLR3-TM and TLR3-TM bind by nuclear magnetic resonance (1, 2)

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Helix-packing motifs in membrane proteins

Cited by 258 publications

References 32 publications

Computational design of a protein crystal

Computational design of a protein crystal

Transmembrane orientation and possible role of the fusogenic peptide from parainfluenza virus 5 (PIV5) in promoting fusion

Toll‐like receptor 3 transmembrane domain is able to perform various homotypic interactions: An NMR structural study

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