SUMF2 (inactive C-alpha-formylglycine-generating enzyme 2) is an endoplasmic-reticulum-luminal paralog of SUMF1/FGE in the sulfatase-modifying-factor family. Unlike SUMF1, which converts an active-site cysteine of newly synthesized sulfatases into C-alpha-formylglycine (activating them), SUMF2 lacks the catalytic cysteine residues and has no formylglycine-generating activity. Its function is regulatory: SUMF2 forms homodimers and heterodimers with SUMF1 and inhibits SUMF1-mediated sulfatase activation, thereby acting as a negative modulator of cellular sulfatase activity (and downstream processes such as glycosaminoglycan and glycosphingolipid catabolism). It is broadly expressed and retained in the ER by canonical and non-canonical retention signals.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: ER localization (IBA); SUMF2 is an ER-luminal protein. Reason: Correct core localization. Supporting Evidence: file:human/SUMF2/SUMF2-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000120 | ACCEPT | Summary: ER lumen localization (IEA). Reason: Correct, supported by UniProt and EXP evidence. Supporting Evidence: file:human/SUMF2/SUMF2-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005515 protein binding | IPI PMID:15962010 Sulphatase activities are regulated by the interaction of su... | KEEP AS NON CORE | Summary: IPI 'protein binding'; the partner is SUMF1. The SUMF2-SUMF1 interaction is the basis of SUMF2's function (it inhibits SUMF1). Falcon deep research corroborates that this regulatory relationship (SUMF1 activating, SUMF2 antagonizing) is the functional core, and structural data (Dickmanns 2005) raise an FGE-pFGE heterodimer as the candidate physical mechanism. Reason: Functionally central interaction, but the generic 'protein binding' term is uninformative; the specific regulatory role is captured by enzyme inhibitor activity and in core_functions. Keep as supporting non-core. Supporting Evidence: file:human/SUMF2/SUMF2-uniprot.txt Inhibits the activation of sulfatases by SUMF1 file:human/SUMF2/SUMF2-deep-research-falcon.md SUMF1 promotes sulfatase activity while SUMF2 inhibits it |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a large neurodegenerative-disease interactome. Reason: High-throughput, uninformative; over-annotation. |
| GO:0005515 protein binding | IPI PMID:32838362 Virus-Host Interactome and Proteomic Survey Reveal Potential... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a SARS-CoV-2 virus-host interactome screen. Reason: High-throughput viral interactome; uninformative about native function; over-annotation. |
| GO:0005515 protein binding | IPI PMID:33845483 Multilevel proteomics reveals host perturbations by SARS-CoV... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a SARS-CoV-2 host-perturbation proteomics screen. Reason: High-throughput; uninformative; over-annotation. |
| GO:0005515 protein binding | IPI PMID:36217030 A comprehensive SARS-CoV-2-human protein-protein interactome... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a comprehensive SARS-CoV-2-human interactome. Reason: High-throughput viral interactome; over-annotation. |
| GO:0042802 identical protein binding | IPI PMID:15962010 Sulphatase activities are regulated by the interaction of su... | KEEP AS NON CORE | Summary: Identical protein binding: SUMF2 forms homodimers. The pFGE crystal structure (Dickmanns 2005, via falcon deep research) directly observes a homodimer in the asymmetric unit. Reason: Real (homodimer) but generic; non-core. Supporting Evidence: file:human/SUMF2/SUMF2-uniprot.txt Homodimer and heterodimer with SUMF1 file:human/SUMF2/SUMF2-deep-research-falcon.md The asymmetric unit of the pFGE crystal contains a homodimer |
| GO:0042802 identical protein binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Identical protein binding (homodimer), IEA. Reason: Consistent with the homodimer; non-core. Supporting Evidence: file:human/SUMF2/SUMF2-uniprot.txt Homodimer and heterodimer with SUMF1 |
| GO:0043687 post-translational protein modification | TAS Reactome:R-HSA-163841 | KEEP AS NON CORE | Summary: Post-translational protein modification (TAS): pathway context of sulfatase Cys->formylglycine maturation that SUMF2 modulates. Reason: Pathway-level context; SUMF2 modulates rather than performs this PTM. Non-core. |
| GO:0046479 glycosphingolipid catabolic process | TAS Reactome:R-HSA-9840310 | KEEP AS NON CORE | Summary: Glycosphingolipid catabolic process (TAS): downstream consequence of sulfatase activity, which SUMF2 indirectly modulates by inhibiting SUMF1. Reason: Indirect/downstream pathway context; non-core. |
| GO:0004857 enzyme inhibitor activity | TAS Reactome:R-HSA-1614336 | ACCEPT | Summary: Enzyme inhibitor activity: SUMF2 inhibits the sulfatase-activating (formylglycine-generating) activity of SUMF1 via heterodimerization. This is SUMF2's defining molecular role. Falcon deep research reinforces that SUMF2/pFGE is catalytically inactive yet binds sulfatase peptides and acts as a negative regulator of sulfatase activation, and that co-expression of pFGE compromises FGE's ability to generate active sulfatases. Reason: Core molecular function. Although catalytically dead as an FGE, SUMF2 acts as a negative regulator (inhibitor) of SUMF1, consistent with the UniProt FUNCTION statement and corroborated by deep-research synthesis of the Dickmanns 2005 structural/co-expression work. Supporting Evidence: file:human/SUMF2/SUMF2-uniprot.txt Inhibits the activation of sulfatases by SUMF1 file:human/SUMF2/SUMF2-deep-research-falcon.md pFGE can compromise the ability of FGE to generate catalytically active sulfatases |
| GO:0005788 endoplasmic reticulum lumen | EXP PMID:18266766 Paralog of the formylglycine-generating enzyme--retention in... | ACCEPT | Summary: ER lumen localization (EXP); SUMF2 is retained in the ER by canonical and non-canonical signals. Reason: Direct experimental support for core localization. Supporting Evidence: file:human/SUMF2/SUMF2-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005783 endoplasmic reticulum | IDA PMID:18266766 Paralog of the formylglycine-generating enzyme--retention in... | ACCEPT | Summary: ER localization (IDA). Reason: Direct experimental support; consistent. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-1614336 | ACCEPT | Summary: ER lumen localization (TAS). Reason: Consistent core localization. |
Loading supporting content…
Download this section (compressed HTML)Q: Is SUMF2's inhibition of SUMF1 physiologically tuned (e.g. tissue-specific SUMF1:SUMF2 ratios) to set sulfatase activity set-points?
Experiment: Titrate SUMF2:SUMF1 expression ratios and measure formylglycine content and activity of multiple client sulfatases (e.g. ARSA, ARSB, SGSH).
Hypothesis: SUMF2 sets a rheostat on cellular sulfatase activation via the SUMF1:SUMF2 ratio.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)