STEAP1 (six-transmembrane epithelial antigen of the prostate 1) is a multi-pass plasma membrane protein of the STEAP metalloreductase family that assembles as a homotrimer. Each protomer has six transmembrane helices with cytoplasmic N- and C-termini and binds a heme b cofactor near the extracellular leaflet. Unlike STEAP2-4, STEAP1 lacks the cytoplasmic NADPH-binding oxidoreductase domain and on its own shows no cellular ferric reductase activity; its transmembrane heme domain can reduce Fe(III) when supplied with electrons from a STEAP4 NADPH domain, suggesting a possible role within STEAP heterotrimers. STEAP1 is expressed mainly in prostate epithelium and is strongly overexpressed at the cell surface of prostate and other cancers, where its extracellular helices are targeted by therapeutic antibodies.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: High-throughput interactome detection of STEAP1B binding. Reason: Generic protein binding is uninformative; removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput interactome detection of STEAP1B binding. Reason: Generic protein binding is uninformative; removal does not dispute the interaction. |
| GO:0005768 endosome | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Endosome inherited from STEAP family members (e.g. STEAP3, mouse Steap proteins). Reason: Plausible endocytic pool, but direct human STEAP1 data show predominantly cell-surface localization. Supporting Evidence: file:human/STEAP1/STEAP1-uniprot.txt Endosome membrane {ECO:0000250|UniProtKB:Q9CWR7} |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane inherited across the STEAP family. Reason: Matches direct human evidence. Supporting Evidence: PMID:10588738 Protein analysis located STEAP at the cell surface of prostate-cancer cell lines. |
| GO:0005886 plasma membrane | IDA PMID:32409586 Cryo-electron microscopy structure and potential enzymatic f... | ACCEPT | Summary: Confocal microscopy shows STEAP1 constructs at the plasma membrane. Reason: Direct evidence; consistent with cryo-EM antibody binding to extracellular helices. Supporting Evidence: PMID:32409586 STEAP1 is an integral membrane protein that is highly up-regulated on the cell surface of several human cancers |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCell cell membrane mapping. Reason: Supported by experimental evidence. Supporting Evidence: PMID:32409586 interacts with the Fabs through its extracellular helices |
| GO:0005886 plasma membrane | TAS PMID:10588738 STEAP: a prostate-specific cell-surface antigen highly expre... | ACCEPT | Summary: Original cloning paper places STEAP at the cell surface of prostate cancer cells. Reason: Consistent with all later evidence. Supporting Evidence: PMID:10588738 Our results support STEAP as a cell-surface tumor-antigen target for prostate cancer therapy |
| GO:0005911 cell-cell junction | TAS PMID:10588738 STEAP: a prostate-specific cell-surface antigen highly expre... | KEEP AS NON CORE | Summary: IHC shows STEAP1 at cell-cell junctions of prostate secretory epithelium. Reason: Reflects lateral plasma membrane staining in epithelium; supported by the paper but not a defined junctional complex role. Supporting Evidence: PMID:10588738 STEAP expression at the cell-cell junctions of the secretory epithelium of prostate and prostate cancer cells |
| GO:0010008 endosome membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt endosome membrane location by similarity to mouse Steap1. Reason: Possible minor intracellular pool; not demonstrated for human STEAP1. Supporting Evidence: file:human/STEAP1/STEAP1-uniprot.txt Endosome membrane {ECO:0000250|UniProtKB:Q9CWR7} |
| GO:0010008 endosome membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Endosome membrane by similarity to mouse Q9CWR7. Reason: Same as above; retained as non-core given predominant surface localization. Supporting Evidence: file:human/STEAP1/STEAP1-uniprot.txt Endosome membrane {ECO:0000250|UniProtKB:Q9CWR7} |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MODIFY | Summary: NK cell membrane proteome. Reason: Correct but general; the specific location supported for STEAP1 is plasma membrane. Proposed replacements: plasma membrane Supporting Evidence: PMID:10588738 Protein analysis located STEAP at the cell surface of prostate-cancer cell lines. |
| GO:0020037 heme binding | IDA PMID:32409586 Cryo-electron microscopy structure and potential enzymatic f... | ACCEPT | Summary: Cryo-EM and spectroscopy show a bis-His-coordinated heme b in the TMD. Reason: Direct structural evidence; heme is the only redox cofactor STEAP1 retains. Supporting Evidence: PMID:32409586 Strictly conserved histidine residues H175 and H268 coordinate the central iron moiety of the heme prosthetic group |
| GO:0052851 ferric-chelate reductase (NADPH) activity | IDA NOT PMID:32409586 Cryo-electron microscopy structure and potential enzymatic f... | ACCEPT | Summary: NOT ferric-chelate reductase (NADPH) activity; STEAP1 alone shows no cellular ferric reductase activity. Reason: The negative annotation is directly supported and explained by absence of the NADPH-binding domain. Supporting Evidence: PMID:32409586 STEAP1 lacks an intracellular NADPH-binding domain and does not exhibit cellular ferric reductase activity |
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Download this section (compressed HTML)Q: Does STEAP1 form heterotrimers with STEAP2 or STEAP4 in native prostate cells, and do these mediate Fe(III)/Cu(II) reduction at the cell surface?
Q: What, if anything, is the physiological electron donor for the STEAP1 heme in the absence of an NADPH domain?
Experiment: Co-immunoprecipitation and native mass spectrometry of endogenous STEAP family proteins in LNCaP cells, combined with cell-surface ferric reductase assays after STEAP1 knockdown.
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