| Concept / paper | Main finding for human ASNA1/TRC40 (GET3) | Pathway components highlighted | Quantitative / statistical points in evidence | URL | Publication date | Citation |
|---|---|---|---|---|---|---|
| Core function overview | Human ASNA1/TRC40 is the metazoan Get3 ortholog: a homodimeric ATPase/chaperone that captures tail-anchored (TA) proteins post-translationally, shields their hydrophobic C-terminal transmembrane domain, and delivers them to the ER for insertion. | Cytosolic TRC40/ASNA1 plus ER receptor/insertase WRB-CAML; upstream pre-targeting factors hand cargo to ATP-bound TRC40. | TA proteins are estimated to comprise ~5% of eukaryotic membrane proteins in one 2023 structural study. | https://doi.org/10.1083/jcb.202105004 ; https://doi.org/10.1038/s41467-023-42867-2 | 2021-07 ; 2023-11 | (pqac-00000002, pqac-00000009) |
| Pathway organization review (Qin 2023 The Innovation Life) | The conserved TRC/GET pathway routes relatively hydrophobic TA proteins to the ER; TRC40/ASNA1 is the central ATPase receiving substrates from the pre-targeting machinery and passing them to the membrane receptor. | SGTA/Sgt2, TRC35/Get4, UBL4A/Get5, BAG6 in mammals; receptor complex WRB and CAML at ER. | No specific numerical result in the excerpt; emphasis is on ordered substrate handoff. | https://doi.org/10.59717/j.xinn-life.2023.100013 | 2023-01 | (pqac-00000013) |
| Structural plasticity of the GET insertase (McDowell 2023 Nat Commun) | Structures of human/thermophilic Get1/Get2/Get3 show conserved insertase architecture, conformational plasticity, and local membrane thinning near a hydrophilic groove that likely lowers the energetic barrier for TA insertion. Get2 first engages Get3/TA, then Get1 promotes Get3 opening, nucleotide release, and cargo transfer. | Get3/TRC40 with Get1/Get2 insertase (human WRB/CAML orthologous system discussed in pathway context). | ~5% of eukaryotic membrane proteins are TA; ~15° coiled-coil rotation reported between variant structures; buried surface area ~190 Ų in one interface description. | https://doi.org/10.1038/s41467-023-42867-2 | 2023-11 | (pqac-00000009, pqac-00000016, pqac-00000017) |
| Channel model for insertion (Heo 2023 Cell Reports) | Get1/2 acts as an insertase/translocase forming a transient aqueous channel in membranes; channel activity helps release the TA substrate from Get3 and enables insertion. ATP binding then displaces Get3 for recycling. | Get3 cargo carrier; Get2 recruits Get3-TA; Get1 coiled-coil promotes substrate release; Get4/5 helps prevent premature rebinding. | Estimated channel diameter ~2.5 nm; hydrophilic tails up to ~30 residues discussed; channel-series frequency decreased ~10-fold and occupancy ~4-fold with Get3 versus BSA; replicates typically 2–5 with mean ± SD and unpaired t tests. | https://doi.org/10.1016/j.celrep.2022.111921 | 2023-01 | (pqac-00000008, pqac-00000010) |
| Human ER client-spectrum analysis (Jung & Zimmermann 2023 IJMS) | Proteomic depletion studies in human cells support that TRC/GET preferentially handles membrane protein precursors with central or C-terminal topogenic sequences, consistent with ASNA1/TRC40 specialization for TA-like or late-emerging hydrophobic segments. | Human TRC pathway components including TRC35 and TRC40, compared with SRP, SND, EMC and Sec61-related pathways. | No single number quoted in the excerpt, but study is based on quantitative mass spectrometry across knockdown/knockout conditions. | https://doi.org/10.3390/ijms241814166 | 2023-09 | (pqac-00000013) |
| Redox switch and stress chaperone role (Dempsey 2024 bioRxiv) | Beyond TA insertion, TRC40 can switch under ATP-depleting oxidative stress into a chaperone that limits protein aggregation; oxidation or thiol alkylation suppresses ATPase-linked TA targeting behavior and promotes stress-protective oligomerization. | TRC40/ASNA1 itself; stress-associated overlap with Hsp70/Hsp110-containing foci in cells. | Oxidative activation tested with 2 mM H2O2/CuCl2; reduced TRC40 is dimeric, oxidized/thiol-blocked TRC40 forms tetramers and higher oligomers; tetramers are the smallest chaperone-active unit. | https://doi.org/10.1101/2024.07.10.602939 | 2024-07 | (pqac-00000001) |
| Proteotoxic stress on pre-targeting complex (Hagiwara 2023 Biochem J) | Proteotoxic stress disrupts BAG6-UBL4A complex integrity, implying that stress can compromise the mammalian pre-targeting machinery required for efficient TA-protein biogenesis upstream of TRC40. | BAG6 and UBL4A (mammalian Get5 homolog), upstream of TRC40/Get3. | No specific number quoted in the excerpt. | https://doi.org/10.1042/bcj20230267 | 2023-10 | (pqac-00000013) |
| Redox/arsenite-related legacy function | ASNA1/TRC40 belongs to the ArsA/Get3 ATPase family and earlier work characterized human hASNA1 as an arsenite-stimulated ATPase; more recent literature emphasizes TA targeting and redox-sensitive switching rather than arsenical pumping in human cells. | ArsA/Get3 family context; human TRC pathway function integrated with ATPase activity. | No additional quantitative value in the excerpt beyond historical classification. | https://doi.org/10.1101/2021.05.03.442402 ; https://doi.org/10.1101/2024.07.10.602939 | 2021-05 ; 2024-07 | (pqac-00000003, pqac-00000006, pqac-00000001) |


*Table: This table condenses the main mechanistic, structural, and stress-response findings for human ASNA1/TRC40 (GET3), with emphasis on 2023-2024 advances. It also captures the pathway components and quantitative data points most useful for functional annotation.*