Structural Determinants of Lateral Gate Opening in the Protein Translocon

Gumbart, James C.; Schulten, Klaus

doi:10.1021/bi700835d

Cited by 62 publications

(64 citation statements)

References 72 publications

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“…Molecular dynamics simulations suggest that plug deletions would allow translocation and lateral gate opening more easily than the native closed Sec61 (31)(32)(33). This agrees with the observation that deletion of the plug negates the requirement of a signal sequence for channel opening (15).…”

Section: General Model For the Priming Of The Translocon For Protein supporting

confidence: 79%

Lateral opening of a translocon upon entry of protein suggests the mechanism of insertion into membranes

Egea

Stroud

2010

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

156

173

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The structure of the protein-translocating channel SecYEβ from Pyrococcus furiosus at 3.1-Å resolution suggests a mechanism for chaperoning transmembrane regions of a protein substrate during its lateral delivery into the lipid bilayer. Cytoplasmic segments of SecY orient the C-terminal α-helical region of another molecule, suggesting a general binding mode and a promiscuous guiding surface capable of accommodating diverse nascent chains at the exit of the ribosomal tunnel. To accommodate this putative nascent chain mimic, the cytoplasmic vestibule widens, and a lateral exit portal is opened throughout its entire length for partition of transmembrane helical segments to the lipid bilayer. In this primed channel, the central plug still occludes the pore while the lateral gate is opened, enabling topological arbitration during early protein insertion. In vivo, a 15 amino acid truncation of the cytoplasmic C-terminal helix of SecY fails to rescue a secY -deficient strain, supporting the essential role of this helix as suggested from the structure.

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Section: General Model For the Priming Of The Translocon For Protein supporting

confidence: 79%

Lateral opening of a translocon upon entry of protein suggests the mechanism of insertion into membranes

Egea

Stroud

2010

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

156

173

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“…16,23,29,30 These models were shown to be successful in predicting bulk material properties 31 as well as in describing molecular level phenomena. [32][33][34] In this paper we explore the effect of hydrophobic mismatch on the cross-angle distribution of simulated TM helices. We simulate a CG model of a TM a-helix that contains no specic residue information and explore its interactions under various hydrophobic mismatch conditions.…”

Section: Introductionmentioning

confidence: 99%

Lipid mediated packing of transmembrane helices – a dissipative particle dynamics study

Benjamini

Smit

2013

Soft Matter

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Interactions of transmembrane (TM) helices play a key role in many cell processes. The configuration and cross angle these helices adopt are traditionally attributed to specific residue interactions. We present a different approach, in which specific residues are disregarded, and the role of the membrane in TM helix packing is investigated. We introduce a coarse-grained model of TM helices and obtain their characteristic configurations in the membrane both as a single helix and as paired helices. Our analysis shows that hydrophobic mismatch has a substantial effect in determining not only the tilt angles of TM helices but also the cross angles between helix pairs, for a large range of hydrophobic mismatches. We discuss the origin of this effect as well as the deviations from the common trend. Additionally, we explore the effect of hydrophobic mismatch on the Potential of Mean Force (PMF) between TM helices and discuss the importance of helical geometry in forming crossed configurations. Our observations suggest that hydrophobic mismatch must be taken into account when analyzing configurations of TM helix pairs. Hydrophobic mismatch through its effect on helix tilt can explain many cross-angle distribution features, making the role of specific interactions in determining helix pair configurations less significant.

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“…Structures of the Sec translocon (7-9) reveal two apparent gates, one transverse for the passage of soluble proteins across the membrane and one lateral for the exit of membrane proteins (7,10,11). The lateral gate is formed at the interface of two halves of SecY (7,12) (see Fig. 1B).…”

mentioning

confidence: 99%

Free-energy cost for translocon-assisted insertion of membrane proteins

Gumbart

Chipot

Schulten

2011

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

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Nascent membrane proteins typically insert in a sequential fashion into the membrane via a protein-conducting channel, the Sec translocon. How this process occurs is still unclear, although a thermodynamic partitioning between the channel and the membrane environment has been proposed. Experiment-and simulationbased scales for the insertion free energy of various amino acids are, however, at variance, the former appearing to lie in a narrower range than the latter. Membrane insertion of arginine, for instance, requires 14-17 kcal∕mol according to molecular dynamics simulations, but only 2-3 kcal∕mol according to experiment. We suggest that this disagreement is resolved by assuming a two-stage insertion process wherein the first step, the insertion into the translocon, is energized by protein synthesis and, therefore, has an effectively zero free-energy cost; the second step, the insertion into the membrane, invokes the translocon as an intermediary between the fully hydrated and the fully inserted locations. Using free-energy perturbation calculations, the effective transfer free energies from the translocon to the membrane have been determined for both arginine and leucine amino acids carried by a background polyleucine helix. Indeed, the insertion penalty for arginine as well as the insertion gain for leucine from the translocon to the membrane is found to be significantly reduced compared to direct insertion from water, resulting in the same compression as observed in the experiment-based scale.membrane-protein insertion | SecY | ribosome | hydrophobicity scale N early all membrane proteins found in the inner membranes of bacterial cells and the membranes of eukaryotic cells are inserted concomitant with their synthesis by the ribosome, i.e., cotranslationally (1). Insertion into the bilayer does not happen directly, but rather occurs via a highly conserved protein-conducting channel in the membrane, the Sec translocon (2-4). At an early stage of synthesis, the ribosome docks to the channel, forming a tightly bound complex (5, 6). The polypeptide is then inserted into the translocon prior to entering the membrane, the former step requiring a driving force, such as nucleotide hydrolysis, a membrane potential gradient, or the pressure exerted by the growing nascent chain (2).In addition to aiding the insertion of membrane proteins, the translocon also allows certain nascent proteins to cross the membrane (2). Structures of the Sec translocon (7-9) reveal two apparent gates, one transverse for the passage of soluble proteins across the membrane and one lateral for the exit of membrane proteins (7,10,11). The lateral gate is formed at the interface of two halves of SecY (7, 12) (see Fig. 1B). This gate fluctuates during translocation of the nascent polypeptide (13,14), although what factors govern its opening and closing are unclear (8,9,15).Given the two pathways presented by the translocon, there must exist a way to discriminate between proteins destined for the lipid membrane environment and proteins destined ...

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Structural Determinants of Lateral Gate Opening in the Protein Translocon

Cited by 62 publications

References 72 publications

Lateral opening of a translocon upon entry of protein suggests the mechanism of insertion into membranes

Lateral opening of a translocon upon entry of protein suggests the mechanism of insertion into membranes

Lipid mediated packing of transmembrane helices – a dissipative particle dynamics study

Free-energy cost for translocon-assisted insertion of membrane proteins

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