9.A.64 The SRP-independent Targeting (SND) Family

Targeting to the endoplasmic reticulum can occur co-translationally by the signal recognition particle (SRP; TC# 3.A.5) pathway or post-translationally by the mammalian transmembrane recognition complex of 40 kDa (TRC40) and homologous yeast guided entry of tail-anchored proteins (GET; 3.A.19) pathways. Many proteins are inserted independently of both SRP and GET (Tirincsi et al. 2021). Aviram et al. 2016 performed a systematic visual screen using the yeast, Saccharomyces cerevisiae, and uncovered three previously uncharacterized proteins whose loss affected targeting. These proteins may work together in parallel with the SRP and GET pathways to target a broad range of substrate proteins to the endoplasmic reticulum. The three proteins, Snd1, Snd2 and Snd3 (for SRP-independent targeting), can compensate for the loss of both the SRP and GET pathways, and act as a backup targeting system. This explains why it had previously not been possible to demonstrate complete loss of targeting for some substrates (Aviram et al. 2016).The Snd2 protein has many eukaryotic homologues, and these proteins comprise the TMEM208 family (TC# 9.B.26).The large (877 aa) Snd1 protein has no apparent TMSs; Snd2 has181 aas and 4 TMSs, and the Snd3 protein has 188 aas and 2 or 3 TMSs.

The generalized reaction catalyzed by the SND proteins is: 

Proteins (cytoplasmic ribosome) → Proteins (ER lumen or membrane)



Aviram, N., T. Ast, E.A. Costa, E.C. Arakel, S.G. Chuartzman, C.H. Jan, S. Haßdenteufel, J. Dudek, M. Jung, S. Schorr, R. Zimmermann, B. Schwappach, J.S. Weissman, and M. Schuldiner. (2016). The SND proteins constitute an alternative targeting route to the endoplasmic reticulum. Nature 540: 134-138.

Haßdenteufel, S., M. Sicking, S. Schorr, N. Aviram, C. Fecher-Trost, M. Schuldiner, M. Jung, R. Zimmermann, and S. Lang. (2017). hSnd2 protein represents an alternative targeting factor to the endoplasmic reticulum in human cells. FEBS Lett. 591: 3211-3224.

Tirincsi, A., M. Sicking, D. Hadzibeganovic, S. Haßdenteufel, and S. Lang. (2021). The Molecular Biodiversity of Protein Targeting and Protein Transport Related to the Endoplasmic Reticulum. Int J Mol Sci 23:.


TC#NameOrganismal TypeExample

The SRP-independent protein to endoplasmic reticulum insertion SND complex, Snd1(877 aas and 0 TMSs), Snd2 (181 aas and 4 TMSs; TMEM208; see 9.B.26) and Snd3 (188 aas and 2 or 3 TMSs). These proteins probably function in an SRP (signal recognition particle)- and GET (guided entry of tail-anchored proteins)-independent pathway for targeting a broad range of substrate proteins to the endoplasmic reticulum. The SND pathway functions in parallel to GET in targeting proteins with downstream hydrophobic motifs (Aviram et al. 2016).

SND pathway of Saccharomyces cerevisiae (Baker's yeast)