SURF1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0033617 mitochondrial respiratory chain complex IV assembly	IBA GO_REF:0000033	ACCEPT	Summary: SURF1 is a well-established assembly factor for mitochondrial Complex IV (cytochrome c oxidase). Phylogenetic inference (IBA) based on conserved function from yeast Shy1 through human SURF1 is strongly supported. The founding paper (PMID:9843204) demonstrated that SURF1 mutations cause COX deficiency and concluded "a role for SURF1 in the biogenesis of the COX complex." Subsequent work confirmed SURF1 as a component of the MITRAC complex that regulates COX assembly (PMID:26321642, PMID:23260140). The deep research review (Guaragnella et al., 2024; Luo et al., 2024) further confirms this as the core conserved function across species. Reason: Mitochondrial respiratory chain complex IV assembly is the core biological process of SURF1. This IBA annotation is well-supported by extensive experimental evidence from multiple organisms and is at the correct level of specificity. SURF1/Shy1 has been consistently identified as a CIV assembly factor across yeast, fission yeast, and human studies. Supporting Evidence: PMID:9843204 These data suggest a role for SURF1 in the biogenesis of the COX complex and define a new class of gene defects causing human neurodegenerative disease. PMID:26321642 The MITRAC complex represents the central assembly intermediate during this process as it receives imported subunits and regulates mitochondrial translation of COX1 mRNA. file:human/SURF1/SURF1-deep-research-falcon.md Functions as a Complex IV (cytochrome c oxidase) assembly factor required for COX1 maturation and COX assembly; implicated in cofactor (heme/Cu) handling during assembly
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: SURF1 is unambiguously a mitochondrial protein. UniProt annotates it to the mitochondrion inner membrane (by sequence similarity to mouse ortholog P09925). The IBA annotation is conservative (mitochondrion rather than mitochondrial inner membrane), which is acceptable. Proteomics data (PMID:34800366) and structural studies from the yeast homolog (Luo et al., 2024) both confirm mitochondrial localization. Reason: Mitochondrial localization is universally agreed upon. While GO:0005743 (mitochondrial inner membrane) is more specific and also present in the annotation set, having the broader mitochondrion annotation from IBA is acceptable as it is phylogenetically well supported. Supporting Evidence: PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase file:human/SURF1/SURF1-deep-research-falcon.md Localizes to the inner mitochondrial membrane with two transmembrane domains and an intermembrane-space (IMS)-facing region
GO:1902600 proton transmembrane transport	IEA GO_REF:0000108	REMOVE	Summary: This IEA annotation was inferred via logical inference from GO:0004129 (cytochrome-c oxidase activity), since cytochrome c oxidase catalyzes proton translocation across the inner mitochondrial membrane. However, SURF1 is NOT a structural subunit of Complex IV and does not itself catalyze proton transport. It is an assembly factor that facilitates the biogenesis of the complex. Proton transmembrane transport is an activity of the assembled Complex IV, not of the assembly factor. Reason: SURF1 does not directly participate in proton transmembrane transport. This annotation derives from the erroneous upstream annotation of cytochrome-c oxidase activity (GO:0004129) to SURF1 via Ensembl Compara. Since SURF1 is an assembly factor and not a catalytic subunit of Complex IV, attributing the catalytic process of proton pumping to SURF1 is incorrect. The assembled complex performs proton translocation; the assembly factor does not.
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: SURF1 localizes to the mitochondrial inner membrane as a multi-pass membrane protein with two predicted transmembrane helices (residues 61-79 and 274-290 per UniProt). UniProt annotates this based on sequence similarity to the mouse ortholog P09925. Experimental work in fission yeast Shy1 confirmed IMM localization by mitochondrial fractionation and protease protection assays (Luo et al., 2024). Reactome also places SURF1 at the inner membrane as part of the MITRAC complex (R-HSA-9865350). Reason: Mitochondrial inner membrane localization is the correct and specific CC annotation for SURF1. This is well-supported by UniProt topology predictions (two TM helices), conservation with yeast Shy1 where inner membrane localization was experimentally confirmed, and Reactome pathway curation. Supporting Evidence: file:human/SURF1/SURF1-deep-research-falcon.md Localizes to the inner mitochondrial membrane with two transmembrane domains and an intermembrane-space (IMS)-facing region (experimental in S. pombe; inferred for human) Reactome:R-HSA-9865350 Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly Complex (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62), COA1 (C7orf44, MITRAC15), COA3 (MITRAC12)...SMIM20 (C4orf52, MITRAC7), and SURF1
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: SURF1 is indeed a membrane protein with two predicted transmembrane helices, placed in the mitochondrial inner membrane. The generic GO:0016020 (membrane) annotation from InterPro domain mapping is not wrong but is very unspecific compared to the more precise GO:0005743 (mitochondrial inner membrane) annotations already present. Reason: While very general, this IEA annotation from InterPro is technically correct. SURF1 contains transmembrane domains and is an integral membrane protein. More specific mitochondrial inner membrane annotations are present from other evidence codes. It is acceptable for an IEA to be broader than what is established by more detailed evidence.
GO:0005515 protein binding	IPI PMID:23260140 MITRAC links mitochondrial protein translocation to respirat...	REMOVE	Summary: This IPI annotation is based on physical interaction between SURF1 and COA3 (Q9Y2R0, also known as MITRAC12), identified in the MITRAC complex dissection study by Mick et al. (2012). The study identified SURF1 as part of the MITRAC complex containing COA3, COX14, and other factors required for early cytochrome c oxidase assembly intermediates. While the interaction is biologically meaningful, 'protein binding' is uninformative. Reason: The term 'protein binding' (GO:0005515) is uninformative per GO curation guidelines. The interaction between SURF1 and COA3 within the MITRAC complex is biologically meaningful and supports SURF1's role in CIV assembly, but this is already captured by the process annotations (GO:0033617). A more informative CC annotation to the MITRAC complex (GO:0062011) would better represent this information. Supporting Evidence: PMID:23260140 we report a comprehensive dissection of early cytochrome c oxidase assembly intermediates containing proteins required for normal mitochondrial translation
GO:0004129 cytochrome-c oxidase activity	IEA GO_REF:0000107	REMOVE	Summary: This IEA annotation was transferred from the mouse ortholog (P09925) via Ensembl Compara. However, SURF1 is NOT a structural or catalytic subunit of cytochrome c oxidase. It is an assembly factor that facilitates the biogenesis of the complex. SURF1 does not itself possess cytochrome-c oxidase enzymatic activity (the catalysis of ferrocytochrome c oxidation coupled to proton pumping). The original paper (PMID:9843204) explicitly states SURF1 encodes "a factor involved in the biogenesis of cytochrome c oxidase," not a subunit with catalytic activity. Reason: This is an incorrect annotation. Cytochrome-c oxidase activity (GO:0004129) describes the catalytic reaction performed by the assembled Complex IV holoenzyme. SURF1 is an assembly factor, not a catalytic subunit. It does not catalyze the reduction of oxygen or pump protons. The Ensembl Compara transfer is erroneous here, likely propagating an annotation from the mouse ortholog that was itself over-annotated. UniProt explicitly describes SURF1 as a "Component of the MITRAC complex that regulates cytochrome c oxidase assembly" (PMID:24027061, PMID:9843204, PMID:26321642), not as having COX catalytic activity. Supporting Evidence: PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. PMID:26321642 The MITRAC complex represents the central assembly intermediate during this process as it receives imported subunits and regulates mitochondrial translation of COX1 mRNA.
GO:0033617 mitochondrial respiratory chain complex IV assembly	IEA GO_REF:0000107	ACCEPT	Summary: This IEA annotation via Ensembl Compara transfers the CIV assembly annotation from the mouse ortholog. Unlike the erroneous cytochrome-c oxidase activity transfer, this annotation is correct: SURF1 does participate in mitochondrial Complex IV assembly. This is consistent with the IBA and IMP annotations for the same term already present. Reason: The Ensembl Compara transfer of Complex IV assembly is correct. This is the core function of SURF1 and is supported by multiple independent evidence lines (IBA, IMP, TAS). The IEA annotation is redundant with these but not incorrect. Supporting Evidence: PMID:9843204 These data suggest a role for SURF1 in the biogenesis of the COX complex
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: SURF1 was identified as part of the high-confidence human mitochondrial proteome by Morgenstern et al. (2021), a comprehensive quantitative proteomics study of the mitochondrial proteome. This HTP evidence confirms mitochondrial localization via mass spectrometry-based identification. Reason: The HTP annotation is based on large-scale quantitative proteomics and is consistent with all other evidence for SURF1 mitochondrial localization. While less specific than the inner membrane annotation, it provides independent experimental support. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865350	ACCEPT	Summary: Reactome places SURF1 at the mitochondrial inner membrane as part of the MITRAC complex in the step where nascent MT-CO1 binds to MITRAC. SURF1 is listed as a subunit of MITRAC alongside CMC1, COX14, COA1, COA3, and SMIM20 (MITRAC7). Reason: The Reactome annotation correctly places SURF1 at the mitochondrial inner membrane, consistent with its topology (two TM helices) and its role as a component of the membrane-bound MITRAC complex. This is well-supported by the Reactome pathway curation. Supporting Evidence: Reactome:R-HSA-9865350 SMIM20 (C4orf52, MITRAC7), and SURF1 (Zhu et al., 1998; Dennerlein et al., 2015).
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865412	ACCEPT	Summary: This Reactome annotation places SURF1 at the inner membrane during the step where TIMM21 carries COX4, COX5A, and COX6C subunits to the MT-CO1:MITRAC complex. SURF1 is part of the MITRAC complex that receives these imported subunits. Reason: Consistent with SURF1 being a component of the inner membrane-bound MITRAC complex that receives imported COX subunits. Duplicate CC annotation from a different Reactome reaction step is acceptable. Supporting Evidence: Reactome:R-HSA-9865412 COX5A and COX6C across the inner membrane, where they bind to the MT-CO1:MITRAC complex
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865449	ACCEPT	Summary: This Reactome annotation places SURF1 at the inner membrane during the copper insertion step into MT-CO1. The Reactome entry for this step describes a metallochaperone complex that inserts Cu2+ into MT-CO1, and SURF1 is present in the broader assembly context at this stage. Reason: Consistent with SURF1 inner membrane localization during the COX assembly pathway. The copper insertion step occurs at the inner membrane where the assembly intermediates reside. Supporting Evidence: Reactome:R-HSA-9865449 A metallochaperone complex... carries a copper cation from the outer side of the inner mitochondrial membrane... to the pre-assembled Complex IV on the inner side of the membrane
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865579	ACCEPT	Summary: This Reactome annotation places SURF1 at the inner membrane during the step where MT-CO1 and MT-CO2 complexes associate and heme moieties are installed. Reactome specifically notes that "the SURF1 subunit of MITRAC may act as an additional chaperone, for which there is evidence in bacterial models." This is a key step where SURF1 may directly facilitate heme a insertion. Reason: Consistent with SURF1 inner membrane localization, and this Reactome entry provides important mechanistic context suggesting SURF1 may function as a heme insertion chaperone during COX assembly. This is well-aligned with the proposed role of SURF1/Shy1 in heme a insertion into COX1. Supporting Evidence: Reactome:R-HSA-9865579 the SURF1 subunit of MITRAC may act as an additional chaperone, for which there is evidence in bacterial models (Smith et al., 2005; Bundschuh et al., 2009). Mutations in SURF1 lead to complex IV deficiency
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865663	ACCEPT	Summary: This Reactome annotation places SURF1 at the inner membrane during the final Complex IV assembly step where MT-CO3, COX6A/B, COX7A, and NDUFA4 bind to the holo-MT-CO1,2 complex. SURF1 is not specifically mentioned in this final step description, suggesting it may no longer be part of the complex at this late stage. Reason: Inner membrane localization is correct for SURF1. While the Reactome entry for this specific step does not explicitly mention SURF1, the protein remains at the inner membrane. The annotation is not wrong, though SURF1 likely acts at earlier assembly stages (COX1 module) rather than this final step. Supporting Evidence: Reactome:R-HSA-9865663 The final assembly of Complex IV consists of binding of the MT-CO3, COX6A, COX6B, COX7A, and NDUFA4 subunits to the holo-MT-CO1, MT-CO2 complex
GO:0005515 protein binding	IPI PMID:26321642 MITRAC7 Acts as a COX1-Specific Chaperone and Reveals a Chec...	REMOVE	Summary: This IPI annotation is based on physical interactions identified in Dennerlein et al. (2015), which found SURF1 interacting with MT-CO1 (P00395), COX6B1 (P14854/P13073), MITRAC7/SMIM20 (Q8N5G0), and COA3/MITRAC12 (Q9Y2R0) within the MITRAC complex. The UniProt INTERACTION section confirms SURF1 interaction with COA3 (6 experiments in IntAct). These are specific interactions within the COX assembly machinery. Reason: While the physical interactions are experimentally validated and biologically meaningful, 'protein binding' (GO:0005515) is uninformative per GO curation guidelines. The interactions of SURF1 with COA3, MITRAC7, and COX1 within the MITRAC complex are better captured by process annotations (GO:0033617) and a CC annotation to the MITRAC pre-assembly complex (GO:0062011). A new CC annotation for the MITRAC complex is proposed below. Supporting Evidence: PMID:26321642 Cytochrome c oxidase, the terminal enzyme of the respiratory chain, is assembled from mitochondria- and nuclear-encoded subunits. The MITRAC complex represents the central assembly intermediate during this process PMID:23260140 we report a comprehensive dissection of early cytochrome c oxidase assembly intermediates containing proteins required for normal mitochondrial translation
GO:0033617 mitochondrial respiratory chain complex IV assembly	IMP PMID:24027061 SURF1 deficiency causes demyelinating Charcot-Marie-Tooth di...	ACCEPT	Summary: This IMP annotation is based on Echaniz-Laguna et al. (2013), which demonstrated that SURF1 mutations cause defective Complex IV assembly and activity. The study identified SURF1 mutations in patients with CMT4 and showed that "complex IV remained partially functional in muscle and fibroblasts" but was reduced, with SURF1 absence confirmed. The c.107-2A>G mutation "produced no normally spliced transcript, leading to SURF1 absence." This is direct mutant phenotype evidence for SURF1 role in CIV assembly. Reason: This is strong IMP evidence demonstrating that loss of SURF1 causes impaired Complex IV assembly. The study shows that SURF1 mutations lead to reduced Complex IV activity and assembly, providing direct genetic evidence for the annotation. This is the core function of SURF1. Supporting Evidence: PMID:24027061 The c.107-2A>G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts. PMID:24027061 encoding an assembly factor of the mitochondrial respiratory chain complex IV
GO:0008535 respiratory chain complex IV assembly	TAS PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytoc...	MODIFY	Summary: This TAS annotation is based on the founding SURF1 paper by Zhu et al. (1998), which identified SURF1 as "a factor involved in the biogenesis of cytochrome c oxidase." GO:0008535 (respiratory chain complex IV assembly) is the parent term of GO:0033617 (mitochondrial respiratory chain complex IV assembly). Since SURF1 specifically functions in the mitochondrial context, the more specific child term GO:0033617 is more appropriate. Reason: GO:0008535 (respiratory chain complex IV assembly) is the broader parent term that also covers bacterial/plasma membrane CIV assembly. Since human SURF1 specifically functions in mitochondrial CIV assembly, the more specific term GO:0033617 (mitochondrial respiratory chain complex IV assembly) is preferred. This term is already annotated via IBA, IEA, and IMP evidence, so this is a specificity refinement. Proposed replacements: mitochondrial respiratory chain complex IV assembly Supporting Evidence: PMID:9843204 These data suggest a role for SURF1 in the biogenesis of the COX complex
GO:0009060 aerobic respiration	TAS PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytoc...	MARK AS OVER ANNOTATED	Summary: This TAS annotation to aerobic respiration is based on the founding SURF1 paper. While SURF1 loss does impair aerobic respiration (because Complex IV is the terminal enzyme of the electron transport chain), SURF1 is an assembly factor, not a direct participant in the respiratory process itself. The aerobic respiration annotation represents an over-annotation; the correct primary annotation is to Complex IV assembly. The downstream consequences of impaired CIV assembly include impaired aerobic respiration, but that does not mean SURF1 is directly "involved_in" aerobic respiration. Reason: SURF1 facilitates the assembly of Complex IV, which is required for aerobic respiration. However, SURF1 does not directly participate in the respiratory chain or electron transport. Annotating an assembly factor to the process carried out by the assembled complex is an over-annotation. The correct annotation is to Complex IV assembly (GO:0033617), which is already present. The relationship between SURF1 and aerobic respiration is indirect (assembly factor -> complex -> process). Supporting Evidence: PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. file:human/SURF1/SURF1-deep-research-falcon.md Functions as a Complex IV (cytochrome c oxidase) assembly factor required for COX1 maturation and COX assembly
GO:0098803 respiratory chain complex	TAS PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytoc...	MODIFY	Summary: This TAS annotation places SURF1 as a component of the "respiratory chain complex." GO:0098803 is defined as "any protein complex that is part of a respiratory chain." SURF1 is NOT a structural subunit of the mature respiratory chain Complex IV. It is an assembly factor that transiently associates with assembly intermediates (MITRAC complex) but is not part of the final assembled complex. The founding paper (PMID:9843204) describes SURF1 as "a factor involved in the biogenesis of cytochrome c oxidase," not as a component of the respiratory chain. Reason: SURF1 is not a structural subunit of the respiratory chain. It is a component of the MITRAC complex, which is a transient assembly intermediate, not the mature respiratory chain complex. The correct CC annotation would be to the mitochondrial respiratory chain complex IV pre-assembly complex (GO:0062011), which describes the MITRAC complex where SURF1 resides. Annotating SURF1 to GO:0098803 (respiratory chain complex) incorrectly implies it is a structural component of the electron transport chain. Proposed replacements: mitochondrial respiratory chain complex IV pre-assembly complex Supporting Evidence: PMID:9843204 SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase PMID:23260140 we report a comprehensive dissection of early cytochrome c oxidase assembly intermediates containing proteins required for normal mitochondrial translation and reveal assembly factors promoting biogenesis of human respiratory-chain complexes PMID:26321642 The MITRAC complex represents the central assembly intermediate during this process as it receives imported subunits and regulates mitochondrial translation of COX1 mRNA.
GO:0062011 mitochondrial respiratory chain complex IV pre-assembly complex	IPI PMID:23260140 MITRAC links mitochondrial protein translocation to respirat...	NEW	Summary: SURF1 is a component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase) complex. This was established by Mick et al. (2012, PMID:23260140), who identified SURF1 as part of early COX assembly intermediates. Dennerlein et al. (2015, PMID:26321642) further confirmed SURF1 presence in the MITRAC complex. UniProt states SURF1 is a "Component of the MITRAC complex." Reactome (R-HSA-9865350) explicitly lists SURF1 as a MITRAC subunit alongside CMC1, COX14, COA1, COA3, and SMIM20. GO:0062011 is defined as "A protein complex that contributes to and regulates mitochondrial respiratory chain complex IV (COX) formation." Reason: This CC annotation is missing from the current annotation set and would accurately capture SURF1's localization within the MITRAC complex. This is more informative than the generic 'respiratory chain complex' (GO:0098803) currently annotated. The MITRAC complex is the specific subcompartment where SURF1 functions, and GO:0062011 was created to describe this complex. Supporting Evidence: PMID:23260140 we report a comprehensive dissection of early cytochrome c oxidase assembly intermediates containing proteins required for normal mitochondrial translation PMID:26321642 The MITRAC complex represents the central assembly intermediate during this process as it receives imported subunits and regulates mitochondrial translation of COX1 mRNA. Reactome:R-HSA-9865350 SMIM20 (C4orf52, MITRAC7), and SURF1 (Zhu et al., 1998; Dennerlein et al., 2015).

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

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