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EcoSal Plus

Domain 4:

Synthesis and Processing of Macromolecules

Targeting and Insertion of Membrane Proteins

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  • Authors: Andreas Kuhn1, Hans-Georg Koch2, and Ross E. Dalbey3
  • Editors: Susan T. Lovett4, Harris D. Bernstein5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Institute for Microbiology and Molecular Biology, University of Hohenheim, 70599 Stuttgart, Germany; 2: Institute for Biochemistry and Molecular Biology, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, 79104, Freiburg, Germany; 3: Department of Chemistry, The Ohio State University, Columbus, OH 43210; 4: Brandeis University, Waltham, MA; 5: National Institutes of Health, Bethesda, MD
  • Received 26 September 2016 Accepted 05 January 2017 Published 07 March 2017
  • Address correspondence to Ross E. Dalbey, dalbey@chemistry.ohio-state.edu
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  • Abstract:

    The insertion and assembly of proteins into the inner membrane of bacteria are crucial for many cellular processes, including cellular respiration, signal transduction, and ion and pH homeostasis. This process requires efficient membrane targeting and insertion of proteins into the lipid bilayer in their correct orientation and proper conformation. Playing center stage in these events are the targeting components, signal recognition particle (SRP) and the SRP receptor FtsY, as well as the insertion components, the Sec translocon and the YidC insertase. Here, we will discuss new insights provided from the recent high-resolution structures of these proteins. In addition, we will review the mechanism by which a variety of proteins with different topologies are inserted into the inner membrane of Gram-negative bacteria. Finally, we report on the energetics of this process and provide information on how membrane insertion occurs in Gram-positive bacteria and . It should be noted that most of what we know about membrane protein assembly in bacteria is based on studies conducted in .

  • Citation: Kuhn A, Koch H, Dalbey R. 2017. Targeting and Insertion of Membrane Proteins, EcoSal Plus 2017; doi:10.1128/ecosalplus.ESP-0012-2016

Key Concept Ranking

Bacterial Proteins
0.5702264
Membrane Protein
0.487228
Outer Membrane Proteins
0.4466876
0.5702264

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ecosalplus.ESP-0012-2016.citations
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/content/journal/ecosalplus/10.1128/ecosalplus.ESP-0012-2016
2017-03-07
2017-09-19

Abstract:

The insertion and assembly of proteins into the inner membrane of bacteria are crucial for many cellular processes, including cellular respiration, signal transduction, and ion and pH homeostasis. This process requires efficient membrane targeting and insertion of proteins into the lipid bilayer in their correct orientation and proper conformation. Playing center stage in these events are the targeting components, signal recognition particle (SRP) and the SRP receptor FtsY, as well as the insertion components, the Sec translocon and the YidC insertase. Here, we will discuss new insights provided from the recent high-resolution structures of these proteins. In addition, we will review the mechanism by which a variety of proteins with different topologies are inserted into the inner membrane of Gram-negative bacteria. Finally, we report on the energetics of this process and provide information on how membrane insertion occurs in Gram-positive bacteria and . It should be noted that most of what we know about membrane protein assembly in bacteria is based on studies conducted in .

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Figures

Image of Figure 1
Figure 1

Single-spanning membrane proteins are classified into three groups. Type 1 proteins span the membrane with the N terminus out and the C terminus in. They can be synthesized as precursor proteins with a cleavable signal sequence (red arrow). Type 2 and 3 both span the membrane with the N terminus in and the C terminus out, but type 3 proteins have their TM region at the C terminus and are specified as tail-anchored proteins. Multispanning proteins span the membrane more than twice.

Citation: Kuhn A, Koch H, Dalbey R. 2017. Targeting and Insertion of Membrane Proteins, EcoSal Plus 2017; doi:10.1128/ecosalplus.ESP-0012-2016
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Image of Figure 2
Figure 2

(A) Cotranslational targeting to the membrane is initiated by binding of the signal recognition particle (SRP) to the hydrophobic sequence protruding from the exit tunnel of the ribosome. The SRP-ribosome nascent chain complex (SRP-RNC) binds to its receptor FtsY at the membrane surface where the nascent chain engages the insertion site (SecYEG, YidC, SecYEG/YidC, or holotranslocon). (B) Bacterial insertion complexes: The holotranslocon with its components SecYEGDF, YidC, and SecA is required for multispanning proteins with large periplasmic domains, whereas SecYEGDF and YidC are sufficient for proteins with small periplasmic regions. YidC alone is capable of inserting small single- and double-spanning proteins. Some proteins can autonomously insert. For all these translocation pathways, most membrane proteins are targeted by SRP and its receptor FtsY.

Citation: Kuhn A, Koch H, Dalbey R. 2017. Targeting and Insertion of Membrane Proteins, EcoSal Plus 2017; doi:10.1128/ecosalplus.ESP-0012-2016
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Figure 3

The SecYEG of is shown (Protein Data Bank [pdb]: 3DIN). Highlighted in the structure are the TM segments of the lateral gate (dark blue) comprising TM2b, TM3, TM7, and TM8 and the plug domain (red), which is thought to seal the channel on the periplasmic side. SecG is displayed in light blue and SecE in green.

Citation: Kuhn A, Koch H, Dalbey R. 2017. Targeting and Insertion of Membrane Proteins, EcoSal Plus 2017; doi:10.1128/ecosalplus.ESP-0012-2016
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Figure 4

The crystal structure of YidC of (adapted from reference 170 ; pdb: 3WVF) has a large periplasmic β-sandwich domain (gold) and a cytoplasmic coiled-coil domain (green). The indicated membrane-spanning helices form a hydrophilic groove with TM3 (purple) and TM5 (red) functioning as a hydrophobic clamp that binds the substrate hydrophobic sequence during its insertion. The substrate contact sites of TM3 and TM5 are highlighted (yellow dots in right panel).

Citation: Kuhn A, Koch H, Dalbey R. 2017. Targeting and Insertion of Membrane Proteins, EcoSal Plus 2017; doi:10.1128/ecosalplus.ESP-0012-2016
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Figure 5

(A) Crystal structure of the SRP (adapted from reference 112 ; pdb: 2XXA). The conserved NG domain of the protein subunit Ffh (54 homologue) is shown in blue and the signal-sequence binding M domain in yellow. The 4.5S RNA is shown in red and the conserved tetraloop and loops A and B are indicated. (B) Crystal structure of the SRP receptor FtsY (pdb: 2QY9). Only the structure of the conserved NG domain is known, while the less conserved N-terminal A domain has not been crystalized so far.

Citation: Kuhn A, Koch H, Dalbey R. 2017. Targeting and Insertion of Membrane Proteins, EcoSal Plus 2017; doi:10.1128/ecosalplus.ESP-0012-2016
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Figure 6

Atomic model of the RNC-bound SRP M and NG domains (adapted from reference 13 ; pdb: 5GAF). The NG domain is shown in blue, the M domain in green, and the 4.5S RNA in gold. The signal anchor sequence (SAS) is displayed in magenta, and the ribosomal protein uL23 is shown in red. The ribosomal surface is shown in grey.

Citation: Kuhn A, Koch H, Dalbey R. 2017. Targeting and Insertion of Membrane Proteins, EcoSal Plus 2017; doi:10.1128/ecosalplus.ESP-0012-2016
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Figure 7

Cartoon showing the individual steps of substrate recognition, targeting, and insertion of membrane proteins by the SRP/SecYEG pathway (step 1). SRP binds to nontranslating ribosomes (grey) and contacts the ribosomal protein uL23 via both NG domain (blue) and M domain (yellow). The C-terminal helix of the M domain (αM5) inserts into the ribosomal tunnel and binds to the intratunnel loop of uL23 (step 1, lower panel) (step 2). When a nascent chain (green) is approaching, the M domain retracts into the distal part of the ribosomal tunnel and the intratunnel loop of uL23 now contacts the nascent chain (step 3). Further chain elongation and full exposure of the signal sequence to the outside of the ribosomal tunnel results in stable SRP binding to the substrate and (step 4) its subsequent targeting to the membrane-bound SRP receptor. The SRP receptor FtsY binds to both lipids and the SecYEG translocon, but only the translocon-bound conformation allows stable contact between the respective NG domains of SRP and FtsY (step 5). Upon interaction of the NG domains of SRP and FtsY, a transient quaternary complex is formed consisting of the SRP-RNC and the SecYEG-bound FtsY. This quaternary complex is primed for nascent chain transfer from the targeting machinery to the SecYEG translocon (step 6). For stable docking of the RNCs onto the SecYEG translocon, SRP dissociates from uL23, which is now free to bind to SecY. Likewise, FtsY dissociates from the cytosolic loops of SecY, which now can contact uL23. These conformational changes allow, on the one hand, the insertion of the nascent chain into the SecY channel, but, on the other hand, also activate the SRP-FtsY complex for GTP hydrolysis. This activation is dependent on the 4.5S RNA (step 7). GTP hydrolysis by the FtsY-SRP complex leads to their dissociation and allows for the next targeting reaction.

Citation: Kuhn A, Koch H, Dalbey R. 2017. Targeting and Insertion of Membrane Proteins, EcoSal Plus 2017; doi:10.1128/ecosalplus.ESP-0012-2016
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Figure 8

(Top) The YidC-only substrates include the simple phage coat proteins of Pf3 (50 amino acids [aa]) and M13 (73 aa), the single-spanning protein TssL (SciP; 217 aa), and the double-spanning proteins mechanosensor protein MscL (138 aa) and subunit c of FF ATP synthase (Fc) (79 aa). (Bottom) The SecYEG substrates include the single-spanning protein FtsQ (276 aa), leader peptidase (LPase) (323 aa), CyoA of the respiration complex (315 aa), subunit a of FF ATP synthase (Fa, 271 aa), and the maltose transporter subunit MalF (514 aa). Fa and MalF require YidC for insertion and folding, respectively.

Citation: Kuhn A, Koch H, Dalbey R. 2017. Targeting and Insertion of Membrane Proteins, EcoSal Plus 2017; doi:10.1128/ecosalplus.ESP-0012-2016
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Figure 9

The single-spanning Pf3 protein binds to the membrane surface where it can then engage the YidC protein. The amino-terminal hydrophilic region of Pf3 coat binds into the groove of YidC, whereas the hydrophobic region is clamped by TM3 and TM5 of YidC and then slides into the membrane interior (greasy slide). During this insertion step, the hydrophilic region dissociates from the groove and is translocated to the periplasm to complete the membrane insertion process. Finally, the fully inserted Pf3 protein is released from YidC into the lipid bilayer.

Citation: Kuhn A, Koch H, Dalbey R. 2017. Targeting and Insertion of Membrane Proteins, EcoSal Plus 2017; doi:10.1128/ecosalplus.ESP-0012-2016
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Figure 10

The crystal structure of SecDF of with the 6-spanning SecD (green) and 6-spanning SecF (gold) (pdb: 3AQP). The arrow highlights the predicted proton conducting channel.

Citation: Kuhn A, Koch H, Dalbey R. 2017. Targeting and Insertion of Membrane Proteins, EcoSal Plus 2017; doi:10.1128/ecosalplus.ESP-0012-2016
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Figure 11

(Top) The N-terminal hairpin of CyoA is inserted by YidC alone, whereas the translocation of the C-terminal periplasmic domain requires SecYEG and SecA. After membrane insertion, the N-terminal signal peptide is cleaved off by signal peptidase 2. (Middle) Fa requires SecYEGDF and YidC for insertion of both the N-terminal and the C-terminal TM segments. (Bottom) The membrane insertion of lactose permease (LacY) requires SecYEGDF. YidC is required for the proper folding of the permease.

Citation: Kuhn A, Koch H, Dalbey R. 2017. Targeting and Insertion of Membrane Proteins, EcoSal Plus 2017; doi:10.1128/ecosalplus.ESP-0012-2016
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Tables

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Table 1

Distinct requirements of Sec-dependent membrane proteins

Citation: Kuhn A, Koch H, Dalbey R. 2017. Targeting and Insertion of Membrane Proteins, EcoSal Plus 2017; doi:10.1128/ecosalplus.ESP-0012-2016

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