3.A.21 The C-terminal Tail-Anchored Membrane Protein Biogenesis/Insertion Complex (TAMP-B) Family of the Guided Entry of Tail-anchored Protein (GET) Superfamily

Sophisticated mechanisms have evolved to target eukaryotic membrane proteins to the correct membrane-surrounded organelle and to protect them from aggregation. Of central importance are cytosolic factors that decode the targeting information of a signal sequence by transient association and escort membrane proteins to their designated location (Schuldiner et al., 2008). Tail-anchored membrane proteins (TA proteins) consist of an N-terminal soluble domain and a single C-terminal transmembrane segment (TMS) (Borgese et al., 2007). The C-terminal localization of their targeting signal requires release of the synthesized protein from the ribosome before interaction with an insertion machinery (Cross et al., 2009). This precludes TA proteins from cotranslational insertion mediated by the signal recognition particle (SRP)-Sec61 translocon system (TC# 3.A.5), which mainly targets membrane proteins with an N-terminal signal sequence.  The tail-anchored assemblly has been studied in unicellular eukaryotes such as Toxoplasma gondii (Padgett et al. 2016), and nuclear localization signals target tail-anchored membrane proteins to the inner nuclear envelope in plants (Groves et al. 2019).  Tail-anchored membrane protein (TA) targeting involves a network of chaperones, cochaperones, and targeting factors that together drive and regulate passage through the cytosol and insertion into the membrane (Shan 2019). Brito et al. 2019 have identified 859, 657 and 119 putative TAMPs in human (Homo sapiens), plant (Arabidopsis thaliana), and yeast (Saccharomyces cerevisiae), respectively, using the TAMPfinder program. Endoplasmic reticulum membrane receptors of the GET pathway seem to be conserved throughout eukaryotes (Asseck et al. 2021). TA protein insertion with a special focus on plants has been reviewed (Mehlhorn et al. 2021).

Although some studies suggest an unassisted insertion of TA proteins into the mitochondrial outer membrane (Meineke et al., 2008), most endoplasmic reticulum (ER)-destined TA proteins are thought to insert by an energy-dependent process, which involves several cytosolic factors. In yeast, it has been shown that the adenosine triphosphatase (ATPase) Get3 (guided-entry of TA proteins-3 pathway) is necessary for the biogenesis of TA proteins (Schuldiner et al., 2008). Get3 is a dimeric protein with each subunit comprising a nucleotide-binding domain (NBD) and a methionine-rich α-helical domain that has been implicated in TA protein binding (TA binding domain, TABD). Mateja et al. 2015 reconstituted the assembly pathway for a functional targeting complex and showed that it comprises a TA protein bound to a Get3 homodimer. Crystal structures of Get3 bound to different TA proteins showed an α-helical TMS occupying a hydrophobic groove that spans the Get3 homodimer. The molecular basis of tail-anchored integral membrane protein recognition by the cochaperone Sgt2 has been studied (Lin et al. 2021), showing that Sgt2 binds to the hydrophobic transmembrane domain of the TA protein.

Crystal structures of Get3 have shown that the protein switches between open and closed states, depending on its nucleotide load. Whereas in the apo and magnesium-free adenosine diphosphate (ADP) forms, the open state is favored (Bozkurt et al., 2009), ADP-Mg2+ and the nonhydrolyzable ATP analog 5′-adenylyl-β,γ-imidodiphosphate-Mg2+ (AMPPNP-Mg2+) induce the closed state, which is further tightened up in the transition state of adenosine triphosphate (ATP) hydrolysis (Mateja et al., 2009). The hydrophobic groove responsible for TA binding seems fully assembled only in the transition state. At the membrane, Get3 interacts with the two receptor proteins, Get1 and Get2, which are essential for TA protein insertion (Schuldiner et al., 2008). 

Tail-anchored (TA) proteins in yeast contain a C-terminal membrane anchor and are posttranslationally delivered to the endoplasmic reticulum (ER) membrane by the Get3 adenosine triphosphatase (an ArsA homologue) interacting with the hetero-oligomeric 3 TMS Get1/2 membrane receptor. Stefer et al. (2011) have determined crystal structures of Get3 in complex with the cytosolic domains of Get1 and Get2 in different functional states. The heterotetrameric Get1/Get2 complex stoichiometry is (Get1)2(Get2)2. The structural data, together with biochemical experiments, show that Get1 and Get2 use adjacent, partially overlapping binding sites and that both can bind simultaneously to Get3. Docking to the Get1/2 complex allows for conformational changes in Get3 that are required for TA protein insertion. A molecular mechanism for nucleotide-regulated delivery of TA proteins was proposed (Stefer et al., 2011).

GET3 cooperates with the HDEL receptor ERD2 to mediate ATP-dependent retrieval of ER proteins that contain a C-terminal HDEL sequence (Schuldiner et al., 2005). This sequence is the retention signal from the Golgi to the ER. It may also be involved in low-level resistance to oxyanions such as arsenite, and in heat tolerance (Shen et al., 2003). It interacts with the Gef1 Cl- transporter in a copper-dependent fashion (Metz et al., 2006). Metz et al. claimed that the arsenite binding site of the E. coli ArsA is not conserved in Arr4p. The homodimer binds to the C-terminus of Gef1p. Both Gef1p and GET3 are required for normal growth under iron-limiting conditions. gef1 mutants lose high-affinity iron uptake because the Fet3p multi-copper oxidase involved in iron uptake (TC #1.A.11.1.1) does not mature normally in a gef1 mutant. This is because copper loading of Fet3p in the lumen of the late secretory pathway requires Cl- which enters the compartment via Gef1p. Therefore, copper and iron are limiting for growth at alkaline pH. Arr4p antagonizes the function of Gef1p (Metz et al., 2006). Thus, Arr4p is a negative regulator of Gef1p which binds directly to the C-terminus of the latter. GET3 (Arr4) thus inhibits Cl- transport via Gef1p (TC #1.A.11.1.1).

The GET complex is composed of the homodimeric Get3 ATPase and its heterooligomeric receptor, Get1/2. During insertion, the Get3 dimer shuttles between open and closed conformational states, coupled with ATP hydrolysis and the binding/release of TA proteins. Kubota et al. (2012) reported crystal structures of ADP-bound Get3 in complex with the cytoplasmic domain of Get1 (Get1CD) in open and semi-open conformations at 3.0- and 4.5-Å resolutions, respectively. Their structures and biochemical data suggest that Get1 uses two interfaces to stabilize the open dimer conformation of Get3. They propose that one interface is sufficient for binding of Get1 by Get3, while the second interface stabilizes the open dimer conformation of Get3.  Evidence supports the conclusion that Get1/2 functions as the insertase directly (Kubota et al. 2012; Wang et al. 2014). Deubiquitinases USP20/33 promote the biogenesis of tail-anchored membrane proteins (Culver and Mariappan 2021).

Entry of newly synthesized TA proteins into the GET pathway in Saccharomyces cerevisiae begins with efficient TMS capture by Sgt2 (a small glutamine-rich tetratricopeptide repeat-containing protein) (Denic 2012). This chaperone shields the TMS after it is released from the ribosome to prevent TA protein aggregation in the cytosol or mistargeting to mitochondria. Sgt2 is in a complex with Get4 and Get5, two pathway components that facilitate TA protein transfer from Sgt2 to Get3, a dimeric/tetrameric ATPase that is the ER membrane targeting factor of the GET pathway. This is achieved, first, when ATP stimulates binding of Get3 to Get4, and this increases the local concentration of Get3 near the TA protein because of the Get4-Get5-Sgt2 bridge. Second, Get4 increases the intrinsic rate of Get3-TA protein complex formation, most likely by making Get3 receptive for TMS binding. ATP binding converts Get3 from an open to a semi-closed state; ATP hydrolysis fully closes the Get3 conformation, creating a composite, hydrophobic groove that cradles the TMS. Tail anchors are sandwiched inside the dimeric Get3, which has a head-to-head arrangement of hydrophobic grooves (Denic 2012).

The structure of the Sgt2/Get5 complex is known (Simon et al. 2013) as is that of Get3 bound to different TA proteins which revealed the α-helical TMS occupying the hydrophobic groove that spans the Get3 homodimer (Mateja et al. 2015). The heterotetrameric Get4/Get5 complex (Get4/5), tethers the co-chaperone Sgt2 to the targeting factor, the Get3 ATPase. Crystal structures of the Get3·Get4/5 complex have also been solved (Gristick et al. 2015). In plants, an RK/ST C-terminal motif is required for targeting of OEP7.2 and a subset of other Arabidopsis tail-anchored proteins to the plastid outer envelope membrane (Teresinski et al. 2018). Two cytochrome b5 forms, b5-ER and b5-RR in animals, which differ only in the charge of the C-terminal region, target the endoplasmic reticulum (ER) or the mitochondrial outer membrane (MOM), respectively. Figueiredo Costa et al. 2018 demonstrated that the MOM is the preferred destination of spontaneously inserting TA proteins, regardless of their C-terminal charge, and revealed a novel, substrate-specific ER-targeting pathway. 

Tail-anchored membrane proteins (TAMPs) are relatively simple membrane proteins, often characterized by a single TMS at their C-terminus. Consequently, the hydrophobic TMS, which acts as a subcellular targeting signal, emerges from the ribosome only after termination of translation, precluding canonical co-translational targeting and membrane insertion. Peschke et al. 2018 identified DjlC (P77359) and Flk (P15286) as bona fide E. coli TAMPs and showed that their TMSs are necessary and sufficient for authentic membrane targeting of the fluorescent reporter mNeonGreen. Using strains conditional for the expression of known E. coli membrane targeting and insertion factors, they showed that the signal recognition particle (SRP), its receptor FtsY, the chaperone DnaK and the insertase YidC are each required for efficient membrane localization of both TAMPs. A close association between the TMS of DjlC and Flk with both the Ffh subunit of SRP and YidC was confirmed.  The hydrophobicity of the TMS correlates with the dependency on SRP for efficient targeting (Peschke et al. 2018). 

Many tail-anchored (TA) membrane proteins are targeted to and inserted into the ER by the `guided entry of tail-anchored proteins' (GET) pathway. This post-translational pathway uses transmembrane-domain selective cytosolic chaperones for targeting, and a dedicated membrane protein complex for insertion. Mateja and Keenan 2018 reviewed the mechanisms underlying each step of the pathway, emphasizing available structural work.  The GET pathway can increase the risk of mitochondrial outer membrane proteins to be mistargeted to the ER (Vitali et al. 2018). While the majority of integral membrane proteins are delivered to the ER membrane via the co-translational SRP-dependent route, tail-anchored proteins employ an alternative, post-translational route that relies on distinct factors such as a cytosolic protein quality control component, SGTA. Leznicki and High 2020 showed that SGTA is selectively recruited to ribosomes synthesising a diverse range of membrane proteins, suggesting that it can act on precursors of the co-translational ER delivery pathway. SGTA is recruited to nascent membrane proteins before their transmembrane domain emerges from the ribosome. Hence, SGTA can capture these aggregation prone regions shortly after their synthesis. SGTA thus complements SRP by reducing the co-translational ubiquitination of proteins with multiple hydrophobic signal sequences. It may act to mask specific transmembrane domains until they engage the ER translocon and become membrane inserted (Leznicki and High 2020).

The tail length of C-terminal transmembrane domains (C-TMDs) determines efficient insertion and assembly of membrane proteins in the ER. Membrane proteins with C-TMS tails shorter than approximately 60 amino acids are poorly inserted into the ER membrane, which suggests that translation is terminated before they are recognized by the Sec61 translocon for insertion (Sun and Mariappan 2020). These C-TMSs with insufficient hydrophobicity are post-translationally recognized and retained by the Sec61 translocon complex, providing a time window for efficient assembly with TMDs from partner proteins. Retained TMSs that fail to assemble with their cognate TMDs are slowly translocated into the ER lumen and are recognized by the ER-associated degradation (ERAD; TC# 3.A.25) pathway for removal. In contrast, C-TMSs with sufficient hydrophobicity or tails longer than approximately 80 residues are quickly released from the Sec61 translocon into the membrane or the ER lumen, resulting in inefficient assembly with partner TMDs. Thus, C-terminal tails harbor crucial signals for both the insertion and assembly of membrane proteins (Sun and Mariappan 2020). Sequence-based features determine tail-anchored membrane protein sorting in eukaryotes. The most inclusive predictor uses both hydrophobicity and C-terminal charge in tandem (Fry et al. 2021).

Tail-anchored (TA) proteins fulfill diverse cellular functions within different organellar membranes. Their characteristic C-terminal TMS renders TA proteins inherently prone to aggregation, necessitating posttranslational targeting. The guided entry of TA proteins (GET in yeast)/transmembrane recognition complex (TRC in humans) pathway represents a major route for TA proteins to the endoplasmic reticulum (ER). Farkas and Bohnsack 2021 reviewed the capture of nascent TA proteins at the ribosome by the GET pathway pretargeting complex and the mechanism of their delivery into the ER membrane by the GET receptor insertase. Several alternative routes by which TA proteins can be targeted to the ER have emerged, raising questions about how selectivity is achieved during TA protein capture. The quality control machineries in the ER and outer mitochondrial membrane for displacing mislocalized TA proteins have been reviewed (Farkas and Bohnsack 2021).

The generalized reaction for the C-terminal tail-anchored membrane insertion complex is:

TAMP (cytoplasm) + ATP   TAMP (membrane inserted) +ADP + Pi

This family belongs to the ArsA ATPase (ArsA) Superfamily.



Asseck, L.Y., D.G. Mehlhorn, J.R. Monroy, M.M. Ricardi, H. Breuninger, N. Wallmeroth, K.W. Berendzen, M. Nowrousian, S. Xing, B. Schwappach, M. Bayer, and C. Grefen. (2021). Endoplasmic reticulum membrane receptors of the GET pathway are conserved throughout eukaryotes. Proc. Natl. Acad. Sci. USA 118:.

Borgese, N., S. Brambillasca, and S. Colombo. (2007). How tails guide tail-anchored proteins to their destinations. Curr. Opin. Cell Biol. 19: 368-375.

Bozkurt, G., G. Stjepanovic, F. Vilardi, S. Amlacher, K. Wild, G. Bange, V. Favaloro, K. Rippe, E. Hurt, B. Dobberstein, and I. Sinning. (2009). Structural insights into tail-anchored protein binding and membrane insertion by Get3. Proc. Natl. Acad. Sci. USA 106: 21131-21136.

Brito, G.C., W. Schormann, S.K. Gidda, R.T. Mullen, and D.W. Andrews. (2019). Genome-wide analysis of Homo sapiens, Arabidopsis thaliana, and Saccharomyces cerevisiae reveals novel attributes of tail-anchored membrane proteins. BMC Genomics 20: 835.

Castillo, R. and M.H. Saier. (2010). Functional Promiscuity of Homologues of the Bacterial ArsA ATPases. Int J Microbiol 2010: 187373.

Cross, B.C., I. Sinning, J. Luirink, and S. High. (2009). Delivering proteins for export from the cytosol. Nat Rev Mol. Cell Biol. 10: 255-264.

Culver, J.A. and M. Mariappan. (2021). Deubiquitinases USP20/33 promote the biogenesis of tail-anchored membrane proteins. J. Cell Biol. 220:.

Denic, V. (2012). A portrait of the GET pathway as a surprisingly complicated young man. Trends. Biochem. Sci. 37: 411-417.

Farkas, &.#.1.9.3.;. and K.E. Bohnsack. (2021). Capture and delivery of tail-anchored proteins to the endoplasmic reticulum. J. Cell Biol. 220:.

Figueiredo Costa, B., P. Cassella, S.F. Colombo, and N. Borgese. (2018). Discrimination between the endoplasmic reticulum and mitochondria by spontaneously inserting tail-anchored proteins. Traffic 19: 182-197.

Fry, M.Y., S.M. Saladi, A. Cunha, and W.M. Clemons, Jr. (2021). Sequence-based features that are determinant for tail-anchored membrane protein sorting in eukaryotes. Traffic 22: 306-318.

Gristick, H.B., M.E. Rome, J.W. Chartron, M. Rao, S. Hess, S.O. Shan, and W.M. Clemons, Jr. (2015). Mechanism of Assembly of a Substrate Transfer Complex during Tail-anchored Protein Targeting. J. Biol. Chem. 290: 30006-30017.

Groves, N.R., J.F. McKenna, D.E. Evans, K. Graumann, and I. Meier. (2019). A nuclear localization signal targets tail-anchored membrane proteins to the inner nuclear envelope in plants. J Cell Sci 132:.

Heo, P., J.A. Culver, J. Miao, F. Pincet, and M. Mariappan. (2023). The Get1/2 insertase forms a channel to mediate the insertion of tail-anchored proteins into the ER. Cell Rep 42: 111921.

Kubota, K., A. Yamagata, Y. Sato, S. Goto-Ito, and S. Fukai. (2012). Get1 stabilizes an open dimer conformation of get3 ATPase by binding two distinct interfaces. J. Mol. Biol. 422: 366-375.

Leznicki, P. and S. High. (2020). SGTA associates with nascent membrane protein precursors. EMBO Rep e48835. [Epub: Ahead of Print]

Lin, K.F., M.Y. Fry, S.M. Saladi, and W.M. Clemons, Jr. (2021). Molecular basis of tail-anchored integral membrane protein recognition by the cochaperone Sgt2. J. Biol. Chem. 100441. [Epub: Ahead of Print]

Mateja, A. and R.J. Keenan. (2018). A structural perspective on tail-anchored protein biogenesis by the GET pathway. Curr. Opin. Struct. Biol. 51: 195-202.

Mateja, A., A. Szlachcic, M.E. Downing, M. Dobosz, M. Mariappan, R.S. Hegde, and R.J. Keenan. (2009). The structural basis of tail-anchored membrane protein recognition by Get3. Nature 461: 361-366.

Mateja, A., M. Paduch, H.Y. Chang, A. Szydlowska, A.A. Kossiakoff, R.S. Hegde, and R.J. Keenan. (2015). Protein targeting. Structure of the Get3 targeting factor in complex with its membrane protein cargo. Science 347: 1152-1155.

McDowell, M.A., M. Heimes, F. Fiorentino, S. Mehmood, &.#.1.9.3.;. Farkas, J. Coy-Vergara, D. Wu, J.R. Bolla, V. Schmid, R. Heinze, K. Wild, D. Flemming, S. Pfeffer, B. Schwappach, C.V. Robinson, and I. Sinning. (2020). Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex. Mol. Cell 80: 72-86.e7.

Mehlhorn, D.G., L.Y. Asseck, and C. Grefen. (2021). Looking for a safe haven: tail-anchored proteins and their membrane insertion pathways. Plant Physiol. 187: 1916-1928.

Meineke, B., G. Engl, C. Kemper, A. Vasiljev-Neumeyer, H. Paulitschke, and D. Rapaport. (2008). The outer membrane form of the mitochondrial protein Mcr1 follows a TOM-independent membrane insertion pathway. FEBS Lett. 582: 855-860.

Metz, J., A. Wächter, B. Schmidt, J.M. Bujnicki, and B. Schwappach. (2006). The yeast Arr4p ATPase binds the chloride transporter Gef1p when copper is available in the cytosol. J. Biol. Chem. 281: 410-417.

Oleinik, N., O. Albayram, M.F. Kassir, F.C. Atilgan, C. Walton, E. Karakaya, J. Kurtz, A. Alekseyenko, H. Alsudani, M. Sheridan, Z.M. Szulc, and B. Ogretmen. (2023). Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects. Aging Cell e13954. [Epub: Ahead of Print]

Onishi, M., S. Nagumo, S. Iwashita, and K. Okamoto. (2018). The ER membrane insertase Get1/2 is required for efficient mitophagy in yeast. Biochem. Biophys. Res. Commun. 503: 14-20.

Padgett, L.R., G. Arrizabalaga, and W.J. Sullivan, Jr. (2016). Targeting of tail-anchored membrane proteins to subcellular organelles in Toxoplasma gondii. Traffic. [Epub: Ahead of Print]

Peschke, M., M. Le Goff, G.M. Koningstein, A. Karyolaimos, J.W. de Gier, P. van Ulsen, and J. Luirink. (2018). SRP, FtsY, DnaK and YidC Are Required for the Biogenesis of the E. coli Tail-Anchored Membrane Proteins DjlC and Flk. J. Mol. Biol. 430: 389-403.

Schuldiner, M., J. Metz, V. Schmid, V. Denic, M. Rakwalska, H.D. Schmitt, B. Schwappach, and J.S. Weissman. (2008). The GET complex mediates insertion of tail-anchored proteins into the ER membrane. Cell 134: 634-645.

Schuldiner, M., S.R. Collins, N.J. Thompson, V. Denic, A. Bhamidipati, T. Punna, J. Ihmels, B. Andrews, C. Boone, J.F. Greenblatt, J.S. Weissman, and N.J. Krogan. (2005). Exploration of the function and organization of the yeast early secretory pathway through an epistatic miniarray profile. Cell 123: 507-519.

Shan, S.O. (2019). Guiding Tail-anchored Membrane Proteins to the ER In a Chaperone Cascade. J. Biol. Chem. [Epub: Ahead of Print]

Shen, J., C.M. Hsu, B.K. Kang, B.P. Rosen, and H. Bhattacharjee. (2003). The Saccharomyces cerevisiae Arr4p is involved in metal and heat tolerance. Biometals 16: 369-378.

Simon, A.C., P.J. Simpson, R.M. Goldstone, E.M. Krysztofinska, J.W. Murray, S. High, and R.L. Isaacson. (2013). Structure of the Sgt2/Get5 complex provides insights into GET-mediated targeting of tail-anchored membrane proteins. Proc. Natl. Acad. Sci. USA 110: 1327-1332.

Stefer, S., S. Reitz, F. Wang, K. Wild, Y.Y. Pang, D. Schwarz, J. Bomke, C. Hein, F. Löhr, F. Bernhard, V. Denic, V. Dötsch, and I. Sinning. (2011). Structural basis for tail-anchored membrane protein biogenesis by the Get3-receptor complex. Science 333: 758-762.

Sun, S. and M. Mariappan. (2020). C-terminal tail length guides insertion and assembly of membrane proteins. J. Biol. Chem. 295: 15498-15510.

Teresinski, H.J., S.K. Gidda, T.N.D. Nguyen, N.J. Marty Howard, B.K. Porter, N. Grimberg, M.D. Smith, D.W. Andrews, J.M. Dyer, and R.T. Mullen. (2018). An RK/ST C-terminal Motif is Required for Targeting of OEP7.2 and a Subset of Other Arabidopsis Tail-Anchored Proteins to the Plastid Outer Envelope Membrane. Plant Cell Physiol. [Epub: Ahead of Print]

Vilardi, F., H. Lorenz, and B. Dobberstein. (2011). WRB is the receptor for TRC40/Asna1-mediated insertion of tail-anchored proteins into the ER membrane. J Cell Sci 124: 1301-1307.

Vitali, D.G., M. Sinzel, E.P. Bulthuis, A. Kolb, S. Zabel, D.G. Mehlhorn, B. Figueiredo Costa, &.#.1.9.3.;. Farkas, A. Clancy, M. Schuldiner, C. Grefen, B. Schwappach, N. Borgese, and D. Rapaport. (2018). The GET pathway can increase the risk of mitochondrial outer membrane proteins to be mistargeted to the ER. J Cell Sci 131:.

Wang, F., C. Chan, N.R. Weir, and V. Denic. (2014). The Get1/2 transmembrane complex is an endoplasmic-reticulum membrane protein insertase. Nature 512: 441-444.

Xu, Y., J. Shen, and Z. Ran. (2020). Emerging views of mitophagy in immunity and autoimmune diseases. Autophagy 16: 3-17.


TC#NameOrganismal TypeExample

The C-terminal tail-anchored (TA) membrane protein biogenesis/insertion complex, Get1/Get2/Get3 (Stefer et al., 2011; Kubota et al. 2012; Wang et al. 2014). The ATPase (Get3) is homologous to ArsA of the arsenite exporters (Castillo and Saier, 2010). Get1 and Get2 but not Get3 are required for mitochondrial autophagy, either because of a requirement for Get1/2-dependent TA protein(s), or because the Get1/2 complex itself acts specifically in mitophagy (Onishi et al. 2018). Get3 serves as a chaparone protein, feeding into Get1/Get2 (McDowell et al. 2020). There appear to be distinctive pathways of mammalian mitophagy (Xu et al. 2020). The Get1/2 insertase forms a channel to mediate the insertion of tail-anchored proteins into the ER (Heo et al. 2023).  Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects (Oleinik et al. 2023).


Get1/Get2/Get3 of Saccharomyces cerevisiae
Get1 (P53192)
Get2 (P40056)
Get3 (Q12154)