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General secretory pathway (Sec-SRP) complex.  A biphasic pulling force may act on TMSs during translocon-mediated membrane integration (Ismail et al. 2012).  Intermediate structures for the insertion of integral membrane proteins have been visualized (Bischoff et al. 2014).  Insertion of the Type II single span (N-terminus, in, C-terminus, out) protein, RodZ, requires only SecYEG, SecA and the pmf, but not SecB, SecDF, YidC or FtsY (Rawat et al. 2015).  The combined effects of ribosome and peptide binding to SecYEG may allow for co-translational membrane insertion of successive transmembrane segments (Ge et al. 2014). SecA penetrates deeply into the SecYEG channel during insertion, contacting transmembrane helices and periplasmic loops (Banerjee et al. 2017).

SecAYEGDF/YajC/Ffh/FtsY/4.5S RNA/FtsE? of E. coli
Ffh (SRP54 homologue)
FtsY (SRP receptor subunit α homologue)
FtsE (ATP-binding protein)

SRP52/SRP43/FtsY of chloroplasts (SRP43 provides specificity to SRP52; crystal structures are known (Stengel et al., 2008). SRP43 and the translocase, Alb3 (2.A.9.2.1), interact directly (Dünschede et al., 2011).  FtsY, but not SRP52 or SRP43, also plays a role in photosystem II repair (Walter et al. 2015). SRP43 is an ATP-independent chaperone containing ankyrin repeats required for the biogenesis of the most abundant class of membrane proteins, the light-harvesting chlorophyll a/b-binding proteins (LHCPs) (McAvoy et al. 2018).

SRP43/SRP54/FtsY of Arabidopsis thaliana
SRP43 (O22265)
SRP54 (P37107)
FtsY (O80842)

SecYEGA complex. 

SecYEGA of Bdellovibrio bacteriovorus
SecY, 442 aas and 10 TMSs
SecE, 125 aas and 3 TMSs
SecG, 161 as and 2 TMSs
SecA, 889 aas and 0 TMSs

The general secratory pathway core components, SecYEGA. There are two cardiolipin (CL) binding sites on the surface of the transmembrane parts of SecY, and these two sites account for the preponderance of functional CL binding to SecYEG. They mediate the roles in ATPase and protein transport activity and confer PMF stimulation of protein transport. It is suggested that the apparent transient nature of the CL interaction might facilitate proton exchange with the Sec machinery, and thereby stimulate protein transport (Corey et al. 2018).

The general secretory pathway (Sec) system of Thermotoga maritima

SecY of Bacillus subtilis

The general secretory pathway. SecA1 is the housekeeping protein; SecA2 is the accessory protein, essential for normal physiology and virulence (Rigel et al., 2009).  The functions of SecA2 have been reviewed (Bensing et al. 2013).

SecA1A2YEGDF-YajC-Ffh-FtsY of Mycobacterium tuberculosis H37rv
SecA1 (P0A5Y8)
SecA2 (P66785)
SecY (P0A5Z2)
SecE (P0A5ZO)
SecG (P66791)
SecD (Q50634)
SecF (Q50635)
YajC (P65025)
Ffh (P66844)
FtsY (P66842)

SecY of Mycoplasma capricolum

SecY of Synechococcus PCC7942 (P0A4H1)

Chloroplastic protein secretion system, SecA1/SecY1(Scy1)/SecY2(Scy2)/SecE1/SecG1. SCY1 and SCY2 share a similar, highly conserved structure with 10 transmembrane domains but are targeted to different membranes: the thylakoids and inner envelope, respectively.Targeting elements in these proteins have been identified (Singhal and Fernandez 2017).

Chloroplastic Sec 61 complex of Arabidopsis thaliana

SecY of Cyanidium caldarium

SecY of Cyanophora paradoxa

General secretory (Sec) pathway including SecYEG (Albers et al. 2006).

SecYEG of Haloarcula (Halobacterium) marismortui
SecY (487aas; P28542)
SecE (59aas; Q5V456)
SecG (53aas; Q5V0J1)
SecD (Q5UXT5)
SecF (Q5UXT6)
SRP54 (Q5UY20)
SRP19 (Q5V5S9)
FtsY (Q5UY25)  

General secretory (Sec) pathway including SecYEG (Albers et al. 2006). The 3-d structure is known at 3.1Å resolution (Egea and Stroud, 2010). Upon binding of a substrate protein as it exits the ribosomal tunnel, the SecY cytoplasmic vestibule may widen, and a lateral exit portal opens while the central plug still occludes the pore.

SecYEG of Pyrococcus furiosus 
SecY (468aas; Q8U019)
SecE (61aas; Q8TZK2)
SecG (56aas; Q8TZH7)
SecD (Q8U4B4)
SecF (Q8U4B5)
SRP54 (Q8U070)
Srp19 (Q8TZT9)
FtsY (Q8U051)

FlhF, SRP-like GTPase protein, of 436 aas.  It is part of the flagellar system, but may also be involved in secretion of a variety of virulence factors (Salvetti et al. 2007).  The crystal structure is known (Bange et al. 2007).  It is required for swarming motility and full virulence (Mazzantini et al. 2016).

FlhF of Bacillus cereus

The SecY/SecG/SecE complex with sizes of 436 aas, 53 aas and 74 aas, respectively.  The 3-d structure has been determined to 3.2 Å resolution (PDB 1RH5).  The SecY (Sec61) protein has an unusual topology with a re-entrant coil-helix-coli domain that regulates the permeability of the translocation pore (Van den Berg et al. 2004).  The structure suggests that one copy of the heterotrimer serves as a functional translocation channel. The alpha-subunit (SecY) has two linked halves, transmembrane segments 1-5 and 6-10, clamped together by the gamma-subunit. A cytoplasmic funnel leading into the channel is plugged by a short helix. Plug displacement can open the channel into an 'hourglass' with a ring of hydrophobic residues at its constriction. This ring may form a seal around the translocating polypeptide, hindering the permeation of other molecules. The structure also suggests mechanisms for signal-sequence recognition and for the lateral exit of transmembrane segments of nascent membrane proteins into lipid, and indicates binding sites for partners that provide the driving force for translocation (Van den Berg et al. 2004).

SecYEG of Methanococcus jannaschii
SecY, 436 aas, Q60175
SecG, 53 aas, P60460
SecE, 74 aas, Q57817

The general secretory pathway (Sec-SRP) complex. The Yet1 and Yet3 proteins interact directly with the Sec translocon (Wilson & Barlowe et al., 2010). The Sss1/Sec61γ protein (80aas) has two domains. The cytosolic domain is required for Sec61p interaction while the transmembrane clamp domain is required to complete activation of the translocon after precursor targeting to Sec61p (Wilkinson et al., 2010). However, the apolar surfrace area determines the efficiency of translocon-mediated membrane-protein integration into the endoplasmic reticulum (Öjemalm et al., 2011). The essential Sec62, Sec63 and non-essential Sec66 and Sec72 proteins may comprise an SRP-independent tetrameric translocon enlisting the lumenal chaperone, BiP/Kar2 to "ratchet" its substrates into the ER (Feldheim and Schekman 1994; Ast et al. 2013). Cytosolic segments of the Sec61 complex important for promoting the structural transition between the closed and open conformations of the complex have been identified (Mandon et al. 2018). Positively charged residues in multiple cytosolic segments, as well as bulky hydrophobic residues in the L6/7-TMS7 junction may be required for cotranslational translocation or integration of membrane proteins by the Sec61 complex (Mandon et al. 2018). The structure of the yeast post-translational Sec complex (Sec61-Sec63-Sec71-Sec72) by cryo-EM shows that Sec63 tightly associates with Sec61 through interactions in cytosolic, transmembrane, and ER-luminal domains, prying open Sec61's lateral gate and translocation pore, and thus activating the channel for substrate engagement.  Sec63 optimally positions binding sites for cytosolic and luminal chaperones in the complex to enable efficient polypeptide translocation (Itskanov and Park 2019). Further, post-translational translocation is mediated by the association of the Sec61 channel with the membrane protein complex, the Sec62-Sec63 complex, and substrates move through the channel by the luminal BiP ATPase. Wu et al. 2019 determined the cryoEM structure of the S. cerevisiae Sec complex, consisting of the Sec61 channel and the Sec62, Sec63, Sec71 and Sec72 proteins. Sec63 causes wide opening of the lateral gate of the Sec61 channel, priming it for the passage of low-hydrophobicity signal sequences into the lipid phase, without displacing the channel's plug domain. Lateral channel opening is triggered by Sec63 interacting both with cytosolic loops in the C-terminal half of Sec61 and transmembrane segments in the N-terminal half of the Sec61 channel. The cytosolic Brl domain of Sec63 blocks ribosome binding to the channel and recruits Sec71 and Sec72, positioning them for the capture of polypeptides associated with cytosolic Hsp70. The structure thus shows how the Sec61 channel is activated for post-translational protein translocation (Wu et al. 2019).

Sec (IISP) translocase of Saccharomyces cerevisiae
Sec61β1 (like SecG of E. coli)
Sec61β2 (like SecG of E. coli)
Sec61γ (SSS1p)
SRP receptor, α-chain
SRP receptor, β-chain
Sec63 (NPL1)
Sec66 (HSS1)
Yet1 (C8ZCA7)
Yet3 (C8Z4J7)

Sec-SRP translocase complex. The BAP29 and BAP31 proteins interact directly with the Sec translocon (Wilson & Barlowe et al., 2010).  SRP68 and SRP72 form a complex with SRP RNA and SRP19.  The SRP68 binding site for the RNA is a tetratricopeptide-like module that bends the RNA and inserts an arginine-rich helix into the major groove to open the conserved 5f RNA loop and remodel the RNA for protein translocation (Grotwinkel et al. 2014).  Sec31 (Sec 31L1; HSPC334; HSPC275) is an outer cage component of the coat protein complex II (COPII) machinery which is recruited to specialized regions of the ER, called ER exit sites (ERES), where it plays a central role in the early secretory pathway. Sec31 also interacts with ALG-2 (Programed cell death protein 6 (PDCD6)) and annexin A11 (AnxA11) (Shibata et al. 2015). The Sec61 translocon mediates poorly efficient membrane insertion of Arg-containing TMSs, but a combination of arginine snorkeling, bilayer deformation, and peptide tilting is sufficient to lower the penalty of Arg insertion to an extent that a hydrophobic TMS with a central Arg residue readily inserts into a membrane (Ulmschneider et al. 2017). Mycolactone is a bacterium-derived macrolide that blocks the biogenesis of a large array of secretory and integral transmembrane proteins through potent inhibition of the Sec61 translocon (Morel et al. 2018). The Sec61α subunit possesses an opening between TMS2b and TMS7, the lateral gate, that is the exit for signal sequences and TMSs of translocating polypeptides to the lipid bilayer (Kida and Sakaguchi 2018).

Sec61-SRP translocase complex of Homo sapiens
Sec61 Subcomplex
Sec61α (isoform 1) (P61619)
Sec61α (isoform 2) (Q9H953)
Sec61β (P60468)
Sec61γ (P60059)
Sec62 (AAB51391)
Sec63 (Q9UGP8)
SRP Subcomplex
SRP9 (Alu 9 kDa RNA binding protein) (P49458)
SRP14 (Alu 14 kDa RNA binding protein) (P37108)
SRP19 (S-domain 19 kDa RNA binding protein) (P09132)
SRP54 (S-domain 54 kDa RNA binding protein) (P61011)
SRP68 (S-domain 68 kDa RNA binding protein) (AAH20238)
SRP72 (S-domain 72 kDa RNA binding protein) (O76094)
Bap29 (Q9UHQ4)
Bap31 (P51572)
Sec31A (O94979)
Alg2 (O75340)
AnnexinA11 (P50995)

Sec61α (3-D structure known) (Azad et al., 2011)

Sec61α of Penicillium ochrochloron (BAL40891)

Uncharacterized protein HeimC3_14120 of 523 aas and 13 apparent TMSs.

Candidatus Heimdallarchaeota
UP of Candidatus Heimdallarchaea archaeon LC_3

The GspB-specific secretory system (accessory Sec system for export of the 286 kDa cell wall-anchored platelet-binding adhesin, GspB) (Bensing and Sullam, 2002; Bensing et al., 2004; Takamatsu et al., 2004, 2005). These extra Sec systems are found in species of Streptococcus, Mycobacterium, and Listeria (Rigel and Braunstein, 2008). A region of approximately 20 residues from the amino-terminal end of mature GspB (the accessory Sec transport or AST domain) is essential, possibly as an α-helix, for SecA2/Y2-dependent transport. This AST domain may be essential, both for targeting to the SecA2/Y2 translocase, and for initiating translocation through the SecY2 channel (Bensing & Sullam et al., 2010).  The functions of SecA2 have been reviewed (Bensing et al. 2013).

Accessory Sec system (SecA2, SecY2, Asp1, Asp2, Asp3, Asp4, Asp5) of Streptococcus gordonii
SecA2 (AAK17001)
SecY2 (AAK16997)
Asp1 (AAK16998)
Asp2 (AAK16999)
Asp3 (AAK17000)
Asp4 (AAY99443)
Asp5 (AAY99444)