Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006511 ubiquitin-dependent protein catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation from phylogenetic inference. San1 is a well-characterized E3 ubiquitin ligase that targets misfolded nuclear proteins for ubiquitin-dependent proteasomal degradation (PMID:15078868, PMID:15797381). This is a core biological process for SAN1. Reason: San1 directly promotes ubiquitin-dependent protein catabolism by ubiquitinating misfolded substrates for proteasomal degradation. This is the central downstream biological outcome of San1 activity. The IBA annotation is fully consistent with the extensive experimental evidence from IDA and IMP annotations for the same term. Supporting Evidence: PMID:15797381 San1p, a ubiquitin-protein ligase that, in conjunction with the ubiquitin-conjugating enzymes Cdc34p and Ubc1p, targets four distinct mutant nuclear proteins for ubiquitination and destruction by the proteasome PMID:15078868 mutant sir4 and spt16 proteins are unstable in SAN1 cells but are stabilized in san1Delta cells
GO:0061630 ubiquitin protein ligase activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for ubiquitin protein ligase activity. San1 contains a RING domain and demonstrates E3 ubiquitin ligase activity both in vitro and in vivo (PMID:15078868, PMID:15797381). GO:0061630 is the preferred term for E3 ligases per GO E3 ligase annotation guidelines, and is more specific than GO:0004842. Reason: San1 is a RING-type E3 ubiquitin-protein ligase. This is the correct and preferred MF term for E3 ligases according to GO annotation guidelines. The IBA annotation is well supported by direct experimental evidence (IDA) for both GO:0004842 and GO:0061630. Supporting Evidence: PMID:15078868 We demonstrate that San1 possesses ubiquitin-protein isopeptide ligase activity in vitro, and the ubiquitin-protein isopeptide ligase activity of San1 is required for its function in vivo PMID:21211726 the yeast nuclear PQC ubiquitin ligase San1 directly recognizes its misfolded substrates via intrinsically disordered N- and C-terminal domains
GO:0005737 cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation for cytoplasmic localization. While San1 is primarily a nuclear protein (PMID:15797381), it also participates in cytoplasmic protein quality control (PMID:20080635). Misfolded cytoplasmic proteins are delivered to nuclear San1 in a chaperone-dependent manner. The cytoplasmic localization may reflect the IBA being inferred from orthologs with broader localization. Reason: San1 is primarily nuclear and requires nuclear localization for function (PMID:15797381). However, San1 does participate in cytoplasmic PQC via chaperone-dependent delivery of cytoplasmic substrates (PMID:20080635). The cytoplasmic role is secondary to the primary nuclear PQC function. The IBA is consistent with the IMP annotation from PMID:20080635. Supporting Evidence: PMID:20080635 Ubr1 and San1 mediate chaperone-dependent ubiquitination of numerous misfolded cytoplasmic proteins PMID:15797381 San1p is nuclear localized and requires nuclear localization for function
GO:0008270 zinc ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation inferred from UniProt keyword mapping for zinc binding. San1 contains a RING-type zinc finger domain (residues 240-280) that coordinates zinc ions, which is essential for its E3 ubiquitin ligase activity. Reason: San1 has a well-characterized RING-type zinc finger domain (PROSITE PS50089, Pfam PF13639). RING domains coordinate two zinc ions via conserved cysteine and histidine residues. This is a structural feature directly tied to San1 core E3 ligase activity. The IEA is a broader annotation than what is represented by the RING domain, but it is correct.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for metal ion binding, a parent of zinc ion binding. San1 binds zinc ions through its RING domain. This is a broader annotation than the zinc ion binding annotation but is not incorrect. Reason: This is a parent term of GO:0008270 (zinc ion binding). While redundant with the more specific zinc ion binding annotation, IEA annotations at a broader level are acceptable and not incorrect. The RING domain of San1 coordinates zinc ions.
GO:0005777 peroxisome	HDA PMID:35563734 Pls1 Is a Peroxisomal Matrix Protein with a Role in Regulati...	REMOVE	Summary: HDA annotation from a high-throughput screen (PMID:35563734) that identified new peroxisomal proteins in yeast using overexpression of proteins under a strong TEF2 promoter. SAN1 is not directly discussed in the paper. This study focused on identifying a new peroxisomal protein Pls1 (Ynl097c-b) and its role in lysine biosynthesis. San1 may have been detected in the screen but appears to be a false positive or artifact of overexpression. Reason: San1 is a well-characterized nuclear protein that requires nuclear localization for function (PMID:15797381). No other study has reported peroxisomal localization for San1. The HDA annotation from PMID:35563734 comes from a high-throughput overexpression screen where proteins were expressed under a strong constitutive promoter, which can lead to mislocalization artifacts. San1 is not mentioned by name in the paper. Given the strong evidence for nuclear localization and the absence of any mechanistic connection to peroxisomal function, this annotation is likely artifactual. Supporting Evidence: PMID:15797381 San1p is nuclear localized and requires nuclear localization for function
GO:0008270 zinc ion binding	RCA PMID:30358795 The cellular economy of the Saccharomyces cerevisiae zinc pr...	ACCEPT	Summary: RCA (Reviewed Computational Analysis) annotation for zinc ion binding from a study of the yeast zinc proteome (PMID:30358795). The study used bioinformatics to identify zinc-binding proteins in yeast and characterized the zinc proteome under replete and deficient conditions. San1 was identified as a zinc-binding protein based on its RING domain. Reason: San1 contains a RING-type zinc finger domain that requires zinc for structural integrity and E3 ligase function. The RCA annotation is consistent with the domain architecture of San1 and the IEA annotation. The RING domain (residues 240-280) is a well-characterized zinc-binding fold. Supporting Evidence: PMID:30358795 The yeast zinc proteome of 582 known or potential zinc-binding proteins was identified using a bioinformatics analysis that combined global domain searches with local motif searches
GO:0004842 ubiquitin-protein transferase activity	IDA PMID:21211726 Disorder targets misorder in nuclear quality control degrada...	ACCEPT	Summary: IDA annotation for ubiquitin-protein transferase activity from Rosenbaum et al. 2011, which demonstrated San1 directly ubiquitinates misfolded substrates. While GO:0061630 (ubiquitin protein ligase activity) is the preferred term for E3 ligases, GO:0004842 is a broader parent that is also correct. Reason: San1 has demonstrated ubiquitin-protein transferase activity. GO:0004842 is a broader term that encompasses E3 ligase activity. While GO:0061630 is preferred for E3 ligases, duplicate annotations with the parent term are acceptable, especially when they have distinct experimental evidence. Supporting Evidence: PMID:21211726 the yeast nuclear PQC ubiquitin ligase San1 directly recognizes its misfolded substrates via intrinsically disordered N- and C-terminal domains
GO:0031249 denatured protein binding	IPI PMID:21211726 Disorder targets misorder in nuclear quality control degrada...	MODIFY	Summary: IPI annotation for denatured protein binding from Rosenbaum et al. 2011. This study demonstrated that San1 directly recognizes misfolded substrates through its intrinsically disordered N- and C-terminal domains. The WITH column indicates interaction with P11978 (Cdc68/Spt16). GO:0031249 is being obsoleted. For San1, the binding is for ubiquitination/degradation targeting, not for chaperone-like protection. GO:0051787 (misfolded protein binding) is a more appropriate replacement. A new term "misfolded protein sensor activity" may be even more appropriate for E3 ligases that recognize misfolded substrates for degradation. Reason: GO:0031249 (denatured protein binding) is being obsoleted. San1 directly binds misfolded proteins through its disordered N- and C-terminal domains, but this binding serves to target substrates for ubiquitin-dependent proteasomal degradation, not for chaperone-like protection or refolding. GO:0051787 (misfolded protein binding) is an existing term that better captures the substrate recognition aspect. Ideally, a new term such as "misfolded protein sensor activity" would be created to distinguish degradation-targeting recognition from chaperone-like binding. Proposed replacements: misfolded protein binding Supporting Evidence: PMID:21211726 the yeast nuclear PQC ubiquitin ligase San1 directly recognizes its misfolded substrates via intrinsically disordered N- and C-terminal domains. These disordered domains are punctuated with small segments of order and high sequence conservation that serve as substrate-recognition sites San1 uses to target its different substrates PMID:15797381 San1p has exquisite specificity for aberrant proteins and does not target the wild-type versions of its mutant substrates
GO:0031249 denatured protein binding	IPI PMID:21211726 Disorder targets misorder in nuclear quality control degrada...	MODIFY	Summary: Second IPI annotation for denatured protein binding from Rosenbaum et al. 2011, with additional WITH/FROM entries (P11978, P32558, P32797) indicating interaction with multiple misfolded substrate proteins. Same modification rationale as the first GO:0031249 annotation. Reason: Same as the other GO:0031249 annotation. GO:0031249 is being obsoleted. The evidence supports San1 directly recognizing misfolded substrates, but for degradation rather than chaperoning. GO:0051787 (misfolded protein binding) is the best available replacement term. Proposed replacements: misfolded protein binding
GO:0006511 ubiquitin-dependent protein catabolic process	IDA PMID:15078868 Sir Antagonist 1 (San1) is a ubiquitin ligase.	ACCEPT	Summary: IDA annotation from Dasgupta et al. 2004, which first demonstrated San1 is an E3 ubiquitin ligase that targets mutant Sir4 and Spt16 proteins for degradation. Mutant sir4 and spt16 proteins were shown to be unstable in SAN1 cells but stabilized in san1-delta cells. Reason: Direct experimental evidence that San1 promotes ubiquitin-dependent degradation of specific substrates (mutant Sir4 and Spt16). This is a core biological process for San1. Supporting Evidence: PMID:15078868 mutant sir4 and spt16 proteins are unstable in SAN1 cells but are stabilized in san1Delta cells
GO:0006511 ubiquitin-dependent protein catabolic process	IDA PMID:15797381 Degradation-mediated protein quality control in the nucleus.	ACCEPT	Summary: IDA annotation from Gardner et al. 2005, which demonstrated San1 targets four distinct mutant nuclear proteins for ubiquitination and destruction by the proteasome, working with E2 enzymes Cdc34 and Ubc1. Reason: Strong direct assay evidence for San1 role in ubiquitin-dependent protein catabolism. Gardner et al. showed San1 ubiquitinates multiple distinct aberrant nuclear proteins for proteasomal degradation. This is the core function of San1 in nuclear PQC. Supporting Evidence: PMID:15797381 San1p, a ubiquitin-protein ligase that, in conjunction with the ubiquitin-conjugating enzymes Cdc34p and Ubc1p, targets four distinct mutant nuclear proteins for ubiquitination and destruction by the proteasome
GO:0006511 ubiquitin-dependent protein catabolic process	IMP PMID:15797381 Degradation-mediated protein quality control in the nucleus.	ACCEPT	Summary: IMP annotation from Gardner et al. 2005, based on mutant phenotype evidence. Loss of SAN1 results in chronic stress response and accumulation of aberrant proteins, indicating its role in ubiquitin-dependent protein catabolism. Reason: Mutant phenotype evidence showing that san1-delta cells have impaired degradation of aberrant nuclear proteins. This complements the IDA evidence from the same study. Supporting Evidence: PMID:15797381 Loss of SAN1 results in a chronic stress response, underscoring its role of protein quality control in the cell
GO:0004842 ubiquitin-protein transferase activity	IDA PMID:15078868 Sir Antagonist 1 (San1) is a ubiquitin ligase.	ACCEPT	Summary: IDA annotation from Dasgupta et al. 2004, which first demonstrated San1 possesses ubiquitin-protein isopeptide ligase activity in vitro and that this activity is required for function in vivo. Reason: Direct biochemical demonstration of San1 ubiquitin-protein transferase activity in vitro. While GO:0061630 is the preferred E3 ligase term, this broader annotation is correct and supported by strong direct assay evidence. Supporting Evidence: PMID:15078868 We demonstrate that San1 possesses ubiquitin-protein isopeptide ligase activity in vitro, and the ubiquitin-protein isopeptide ligase activity of San1 is required for its function in vivo
GO:0004842 ubiquitin-protein transferase activity	IDA PMID:15797381 Degradation-mediated protein quality control in the nucleus.	ACCEPT	Summary: IDA annotation from Gardner et al. 2005, confirming San1 is a ubiquitin-protein ligase that ubiquitinates aberrant nuclear proteins in conjunction with Cdc34 and Ubc1. Reason: Independent experimental confirmation of San1 ubiquitin-protein transferase activity, demonstrating it works with specific E2 enzymes (Cdc34 and Ubc1) to ubiquitinate misfolded substrates. Supporting Evidence: PMID:15797381 San1p, a ubiquitin-protein ligase that, in conjunction with the ubiquitin-conjugating enzymes Cdc34p and Ubc1p, targets four distinct mutant nuclear proteins for ubiquitination and destruction by the proteasome
GO:0005634 nucleus	IDA PMID:15797381 Degradation-mediated protein quality control in the nucleus.	ACCEPT	Summary: IDA annotation for nuclear localization from Gardner et al. 2005. San1 is nuclear localized and requires nuclear localization for its protein quality control function. Reason: San1 is primarily a nuclear E3 ligase. Nuclear localization was directly demonstrated and shown to be required for San1 protein quality control function. This is the primary subcellular localization for San1. Supporting Evidence: PMID:15797381 San1p is nuclear localized and requires nuclear localization for function
GO:0005737 cytoplasm	IMP PMID:20080635 Cytoplasmic protein quality control degradation mediated by ...	KEEP AS NON CORE	Summary: IMP annotation for cytoplasmic localization from Heck et al. 2010. This study showed that San1 participates in cytoplasmic PQC alongside Ubr1, where misfolded cytoplasmic proteins are delivered to nuclear San1 via chaperone-dependent mechanisms. Reason: While San1 is primarily nuclear, this study demonstrated a functional role for San1 in cytoplasmic PQC. The mechanism involves chaperone-dependent delivery of misfolded cytoplasmic proteins to nuclear San1, rather than San1 itself operating in the cytoplasm. The cytoplasmic role is secondary to the core nuclear PQC function. Supporting Evidence: PMID:20080635 Ubr1 and San1 mediate chaperone-dependent ubiquitination of numerous misfolded cytoplasmic proteins
GO:0051788 response to misfolded protein	IMP PMID:15797381 Degradation-mediated protein quality control in the nucleus.	ACCEPT	Summary: IMP annotation for response to misfolded protein from Gardner et al. 2005. Loss of SAN1 results in a chronic stress response, indicating San1 plays a role in the cellular response to misfolded proteins. San1 specifically targets aberrant (misfolded) proteins for degradation and does not target wild-type proteins. Reason: San1 is a key component of the nuclear response to misfolded proteins. It specifically recognizes aberrant proteins and targets them for proteasomal degradation. Loss of San1 results in accumulation of misfolded proteins and chronic stress, directly demonstrating its role in this response. Supporting Evidence: PMID:15797381 San1p has exquisite specificity for aberrant proteins and does not target the wild-type versions of its mutant substrates
GO:0071630 nuclear protein quality control by the ubiquitin-proteasome system	IMP PMID:20080635 Cytoplasmic protein quality control degradation mediated by ...	ACCEPT	Summary: IMP annotation for nuclear protein quality control by the ubiquitin-proteasome system from Heck et al. 2010. This study, together with Gardner et al. 2005, established San1 as the defining E3 ligase of the nuclear PQC pathway. San1 ubiquitinates misfolded nuclear proteins for proteasomal degradation. Reason: This is arguably the most specific and informative BP annotation for San1. San1 is the prototypical E3 ligase of nuclear PQC via the ubiquitin-proteasome system. The term precisely captures San1 core biological role. Supporting Evidence: PMID:20080635 Ubr1 and San1 mediate chaperone-dependent ubiquitination of numerous misfolded cytoplasmic proteins PMID:15797381 We propose that San1p-mediated degradation acts as the last line of proteolytic defense against the deleterious accumulation of aberrant proteins in the nucleus
GO:0016567 protein ubiquitination	IDA PMID:15078868 Sir Antagonist 1 (San1) is a ubiquitin ligase.	NEW	Summary: San1 is a RING-type E3 ubiquitin ligase that ubiquitinates misfolded nuclear proteins. According to GO E3 ligase annotation guidelines, the BP for E3 ligases should include protein ubiquitination (GO:0016567) or a more specific child term. This annotation is not currently in the GOA but is warranted based on the guidelines and experimental evidence. Reason: Per GO E3 ubiquitin ligase annotation guidelines, the BP activity unit for an E3 ligase should include protein ubiquitination (GO:0016567) as a part_of annotation. San1 has been directly demonstrated to ubiquitinate substrates in vitro and in vivo (PMID:15078868, PMID:15797381, PMID:21211726). This is a core process annotation that is currently missing. Supporting Evidence: PMID:15078868 We demonstrate that San1 possesses ubiquitin-protein isopeptide ligase activity in vitro, and the ubiquitin-protein isopeptide ligase activity of San1 is required for its function in vivo

Core Functions

E3 ubiquitin-protein ligase activity for nuclear protein quality control. San1 ubiquitinates misfolded nuclear proteins for proteasomal degradation via its RING domain, working with E2 enzymes Cdc34 and Ubc1.

Molecular Function:

ubiquitin protein ligase activity

Directly Involved In:

nuclear protein quality control by the ubiquitin-proteasome system protein ubiquitination ubiquitin-dependent protein catabolic process

Cellular Locations:

nucleus

Supporting Evidence:

PMID:15078868
We demonstrate that San1 possesses ubiquitin-protein isopeptide ligase activity in vitro
PMID:15797381
San1p, a ubiquitin-protein ligase that, in conjunction with the ubiquitin-conjugating enzymes Cdc34p and Ubc1p, targets four distinct mutant nuclear proteins for ubiquitination and destruction by the proteasome

Direct recognition of misfolded proteins via intrinsically disordered N- and C-terminal domains containing conserved substrate-recognition sites. San1 directly binds misfolded substrates with exquisite specificity for aberrant vs. wild-type proteins.

Molecular Function:

misfolded protein binding

Directly Involved In:

response to misfolded protein

Cellular Locations:

nucleus

Supporting Evidence:

PMID:21211726
San1 directly recognizes its misfolded substrates via intrinsically disordered N- and C-terminal domains
PMID:15797381
San1p has exquisite specificity for aberrant proteins and does not target the wild-type versions of its mutant substrates

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

PMID:15078868

Sir Antagonist 1 (San1) is a ubiquitin ligase.

San1 contains a RING domain and possesses ubiquitin-protein isopeptide ligase activity in vitro. Mutant sir4 and spt16 proteins are unstable in SAN1 cells but stabilized in san1-delta cells.

"We demonstrate that San1 possesses ubiquitin-protein isopeptide ligase activity in vitro, and the ubiquitin-protein isopeptide ligase activity of San1 is required for its function in vivo"
San1 targets a specific class of unstable nuclear proteins for degradation. Wild-type Spt16, Sir3, Sir2, and Ste6-166 are not affected by san1-delta.

"san1Delta did not affect the stability of wild-type Spt16, Sir3, Sir2, or the Spt16-associated proteins Pob3 and Nhp6. Loss of SAN1 also did not affect the stability of Ste6-166, a highly unstable protein in yeast"

PMID:15797381

Degradation-mediated protein quality control in the nucleus.

San1 defines a nuclear protein quality control degradation system. It targets four distinct mutant nuclear proteins for ubiquitination and proteasomal destruction, working with E2 enzymes Cdc34 and Ubc1.

"San1p, a ubiquitin-protein ligase that, in conjunction with the ubiquitin-conjugating enzymes Cdc34p and Ubc1p, targets four distinct mutant nuclear proteins for ubiquitination and destruction by the proteasome"
San1 is nuclear localized and requires nuclear localization for function. It has exquisite specificity for aberrant proteins and does not target wild-type versions.

"San1p has exquisite specificity for aberrant proteins and does not target the wild-type versions of its mutant substrates. San1p is nuclear localized and requires nuclear localization for function"
Loss of SAN1 results in a chronic stress response, indicating its essential role in nuclear protein quality control.

"Loss of SAN1 results in a chronic stress response, underscoring its role of protein quality control in the cell"

PMID:20080635

Cytoplasmic protein quality control degradation mediated by parallel actions of the E3 ubiquitin ligases Ubr1 and San1.

San1 also participates in cytoplasmic PQC alongside Ubr1. Two strategies are employed: chaperone-assisted ubiquitination by Ubr1 and chaperone-dependent delivery to nuclear San1.

"Ubr1 and San1 mediate chaperone-dependent ubiquitination of numerous misfolded cytoplasmic proteins"

PMID:21211726

Disorder targets misorder in nuclear quality control degradation: a disordered ubiquitin ligase directly recognizes its misfolded substrates.

San1 directly recognizes misfolded substrates via intrinsically disordered N- and C-terminal domains, which contain conserved substrate-recognition sites interspersed among flexible disordered regions.

"the yeast nuclear PQC ubiquitin ligase San1 directly recognizes its misfolded substrates via intrinsically disordered N- and C-terminal domains. These disordered domains are punctuated with small segments of order and high sequence conservation that serve as substrate-recognition sites"
The intrinsic plasticity of San1 disordered domains allows it to bind many differently shaped misfolded substrates, explaining its broad substrate specificity.

"these substrate-recognition sites, interspersed among flexible, disordered regions, provide San1 an inherent plasticity which allows it to bind its many, differently shaped misfolded substrates"

PMID:30358795

The cellular economy of the Saccharomyces cerevisiae zinc proteome.

San1 was identified as a zinc-binding protein in the yeast zinc proteome analysis, consistent with its RING-type zinc finger domain.

"The yeast zinc proteome of 582 known or potential zinc-binding proteins was identified using a bioinformatics analysis"

PMID:35563734

Pls1 Is a Peroxisomal Matrix Protein with a Role in Regulating Lysine Biosynthesis.

High-throughput screen for peroxisomal proteins using overexpression under strong TEF2 promoter. San1 is not discussed by name in the paper; the HDA annotation for peroxisomal localization may be an artifact of overexpression.

"we utilized a collection of strains containing a peroxisomal marker in which each protein is expressed from the constitutive and strong TEF2 promoter"

📚 Additional Documentation

Deep Research Falcon

(SAN1-deep-research-falcon.md)

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gene_id: SAN1
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protein_description: 'RecName: Full=Protein SAN1;'
gene_info: Name=SAN1; OrderedLocusNames=YDR143C; ORFNames=YD2943.02C;
organism_full: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
protein_family: Not specified in UniProt
protein_domains: Znf_RING. (IPR001841); Znf_RING/FYVE/PHD. (IPR013083); zf-RING_2
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P22470
Protein Description: RecName: Full=Protein SAN1;
Gene Information: Name=SAN1; OrderedLocusNames=YDR143C; ORFNames=YD2943.02C;
Organism (full): Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
Protein Family: Not specified in UniProt
Key Domains: Znf_RING. (IPR001841); Znf_RING/FYVE/PHD. (IPR013083); zf-RING_2 (PF13639)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SAN1" matches the protein description above
Verify the organism is correct: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'SAN1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene SAN1 (gene ID: SAN1, UniProt: P22470) in yeast.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P22470
Protein Description: RecName: Full=Protein SAN1;
Gene Information: Name=SAN1; OrderedLocusNames=YDR143C; ORFNames=YD2943.02C;
Organism (full): Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
Protein Family: Not specified in UniProt
Key Domains: Znf_RING. (IPR001841); Znf_RING/FYVE/PHD. (IPR013083); zf-RING_2 (PF13639)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SAN1" matches the protein description above
Verify the organism is correct: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene SAN1 (gene ID: SAN1, UniProt: P22470) in yeast.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research plan and approach
We verified the identity and organism of the target as the budding yeast protein San1 encoded by SAN1/YDR143C, widely described in the literature as a nuclear RING E3 ubiquitin ligase that mediates nuclear protein quality control (PQC). We then prioritized recent (2023–2024) reviews and primary work on nuclear PQC and San1, and complemented these with authoritative reviews to define function, localization, mechanism, pathway components, and context in stress/quiescence. Where available, URLs and publication dates are provided.

Key concepts and definitions (current understanding)
- Identity and domains: San1 is a nuclear-localized ubiquitin E3 ligase in Saccharomyces cerevisiae that targets misfolded proteins for degradation by the ubiquitin–proteasome system (UPS). It possesses a RING E3 ligase module and is largely intrinsically disordered outside the catalytic domain; these IDRs support recognition of misfolded substrates (exposed hydrophobic segments) (reviewed in 2024 and 2021) (magnati2024neverfoldto pages 4-6, magnati2024neverfoldto pages 2-4, breckel2021ubiquitinligaseredundancy pages 4-6).
- Primary function: San1 catalyzes ubiquitination of misfolded nuclear proteins, thereby directing them to nuclear proteasomes for degradation; it was the first E3 defined for nuclear PQC in yeast and distinguishes mutant/misfolded variants from their native counterparts (2018 authoritative review) (enam2018proteinqualitycontrol pages 7-8).
- Substrate recognition: San1 recognizes a “window of hydrophobicity,” typically short stretches of exposed hydrophobic residues arising in misfolded proteins; its extensive IDRs facilitate autonomous binding to diverse misfolded clients (reviews 2021 and 2024) (breckel2021ubiquitinligaseredundancy pages 4-6, magnati2024neverfoldto pages 4-6, magnati2024neverfoldto pages 2-4).
- Localization and routing: San1 acts in the nucleus. Multiple PQC pathways funnel certain misfolded cytosolic proteins into the nucleus for San1-dependent ubiquitination and proteasomal degradation, underscoring nuclear PQC as a central proteostasis hub (2018 and 2021 reviews) (enam2018proteinqualitycontrol pages 7-8, breckel2021ubiquitinligaseredundancy pages 4-6).
- E2 partners and ubiquitin linkages: San1 primarily acts with E2 Ubc1 in yeast nuclear PQC; ubiquitinated substrates are typically cleared by the 26S proteasome, with proteolytic chains commonly involving proteasome-targeting linkages (general UPS principles summarized in 2024 review) (breckel2021ubiquitinligaseredundancy pages 4-6, magnati2024neverfoldto pages 4-6).

Recent developments (2023–2024) and latest research
- IDR-centric E3 recognition: A 2024 perspective synthesizes accumulating evidence that IDRs are pervasive in PQC factors, highlighting San1 as an E3 that autonomously detects misfolded proteins via IDR-enabled recognition of exposed hydrophobics, and situates San1 within the broader ubiquitin code and proteasome targeting logic (Biophysica, Mar 2024; https://doi.org/10.3390/biophysica4020011) (magnati2024neverfoldto pages 4-6, magnati2024neverfoldto pages 2-4).
- PQC during quiescence: A 2025 JBC article (preprint DOI from 2024) demonstrates that quiescent yeast maintain active degradation-mediated PQC and continue to utilize San1- and Ubr1-dependent ubiquitination; for some model substrates, Ubr1 assumes a dominant role in quiescence, whereas San1’s contribution is reduced, potentially reflecting impaired nuclear delivery or chaperone availability in this state (JBC, Jun 2025; preprint DOI Jun 2024; https://doi.org/10.1101/2024.06.29.601343) (franic2025quiescentcellsmaintain pages 4-7, franic2025quiescentcellsmaintain pages 9-12).

Current applications and real-world implementations
- Reporter-based PQC assays: San1’s activity is routinely assayed with model misfolded reporters and temperature-sensitive substrates to read out ubiquitination and proteasome-dependent turnover in live cells, including in comparisons of exponential growth vs quiescence and in genetic backgrounds that perturb routing or degradation (JBC, 2025; preprint DOI 2024; https://doi.org/10.1101/2024.06.29.601343) (franic2025quiescentcellsmaintain pages 4-7, franic2025quiescentcellsmaintain pages 9-12).
- Nuclear proteostasis frameworks: Recent expert syntheses position San1 as a canonical nuclear PQC E3, shaping experimental design for studies that route cytosolic misfolded proteins into the nucleus for clearance—approaches now commonly used to dissect chaperone and E3 contributions to proteostasis (Annu Rev Biochem, Jun 2018; https://doi.org/10.1146/annurev-biochem-062917-012730; Biomolecules, Dec 2021; https://doi.org/10.3390/biom11121821) (enam2018proteinqualitycontrol pages 7-8, breckel2021ubiquitinligaseredundancy pages 4-6).

Expert opinions and analysis (authoritative sources)
- Enam et al. (2018) provide a definitive review of nuclear PQC degradation, establishing San1 as the founding yeast nuclear PQC E3 ligase that selectively ubiquitinates misfolded nuclear proteins and targets them to nuclear proteasomes (Annu Rev Biochem, Jun 2018; https://doi.org/10.1146/annurev-biochem-062917-012730) (enam2018proteinqualitycontrol pages 7-8).
- Breckel & Hochstrasser (2021) emphasize San1’s nuclear localization, reliance on E2 Ubc1, and the “window of hydrophobicity” substrate rule, while underscoring redundancy with other E3s and the role of nuclear routing of cytosolic clients (Biomolecules, Dec 2021; https://doi.org/10.3390/biom11121821) (breckel2021ubiquitinligaseredundancy pages 4-6).
- Magnati & Bracco (2024) argue that IDR-rich E3s like San1 exemplify how intrinsic disorder enables broad misfolded-protein recognition and interface with ubiquitin chain topologies that prioritize proteasomal clearance (Biophysica, Mar 2024; https://doi.org/10.3390/biophysica4020011) (magnati2024neverfoldto pages 4-6, magnati2024neverfoldto pages 2-4).

Relevant statistics and data from recent studies
- Maintenance of degradation in quiescence: Misfolded model substrates were still selectively degraded in quiescent cells, requiring functional 26S proteasomes; dependence on San1 versus Ubr1 was substrate- and state-specific (with Ubr1 dominance for certain substrates in quiescence), and some substrates additionally required nucleus–vacuole junctions and autophagy for efficient clearance (JBC, Jun 2025; preprint DOI Jun 2024; https://doi.org/10.1101/2024.06.29.601343) (franic2025quiescentcellsmaintain pages 4-7, franic2025quiescentcellsmaintain pages 9-12).
- Substrate feature rule: Reviews synthesizing genetic and biochemical studies report that San1 recognizes short hydrophobic motifs (“windows of hydrophobicity”) generally at least five hydrophobic residues long—a key determinant enabling discrimination of misfolded vs native proteins (Biomolecules, Dec 2021; https://doi.org/10.3390/biom11121821) (breckel2021ubiquitinligaseredundancy pages 4-6).

Mechanistic pathway (function, localization, partners, and substrates)
- Localization: San1 requires nuclear localization (bipartite NLS reported in reviews) and functions in nuclear PQC to ubiquitinate misfolded proteins, which are then degraded by nuclear proteasomes (reviews 2018 and 2021) (enam2018proteinqualitycontrol pages 7-8, breckel2021ubiquitinligaseredundancy pages 4-6).
- E2 partners: San1 primarily cooperates with the E2 Ubc1 in vivo during nuclear PQC; other E3s in the PQC network often partner with Ubc4/Ubc5, but San1’s principal pairing with Ubc1 is emphasized in nuclear PQC summaries (Biomolecules, Dec 2021; https://doi.org/10.3390/biom11121821) (breckel2021ubiquitinligaseredundancy pages 4-6).
- Substrate recognition: San1’s intrinsically disordered regions provide a flexible interface to bind exposed hydrophobic patches—short linear hydrophobic motifs—on misfolded proteins; this recognition rule underlies its broad, autonomous targeting spectrum (Biophysica, Mar 2024; Biomolecules, Dec 2021; https://doi.org/10.3390/biophysica4020011; https://doi.org/10.3390/biom11121821) (magnati2024neverfoldto pages 4-6, magnati2024neverfoldto pages 2-4, breckel2021ubiquitinligaseredundancy pages 4-6).
- Canonical substrates/examples: San1 targets numerous misfolded nuclear proteins and can act on certain cytosolic substrates routed to the nucleus. Recent work used model misfolded proteins (e.g., tGnd1 and stGnd1) to demonstrate San1’s contribution relative to Ubr1 across growth states, with differential reliance in quiescence (JBC, Jun 2025; preprint DOI Jun 2024; https://doi.org/10.1101/2024.06.29.601343) (franic2025quiescentcellsmaintain pages 4-7, franic2025quiescentcellsmaintain pages 9-12).
- Downstream degradation machinery: Polyubiquitinated substrates are degraded by the 26S proteasome; expert reviews specify San1’s role as an upstream ubiquitination factor within nuclear PQC leading to proteasomal clearance (Annu Rev Biochem, Jun 2018; Biophysica, Mar 2024; https://doi.org/10.1146/annurev-biochem-062917-012730; https://doi.org/10.3390/biophysica4020011) (enam2018proteinqualitycontrol pages 7-8, magnati2024neverfoldto pages 4-6).
- Physiological/stress contexts: San1 participates in PQC during both exponential growth and quiescence; in quiescence, proteasomes remain active and PQC integrates proteasome, autophagy, and nucleus–vacuole junction (NVJ)-dependent routes, with San1 and Ubr1 acting in parallel and substrate-dependent fashion (JBC, Jun 2025; preprint DOI Jun 2024; https://doi.org/10.1101/2024.06.29.601343) (franic2025quiescentcellsmaintain pages 4-7, franic2025quiescentcellsmaintain pages 9-12).

Embedded evidence summary
| Study (first author, year) | Source / Type | Main finding about San1 (with citation) | Aspect | Model / Assay | URL | Publication date (month/year) |
|---|---|---|---|---|---|---|
| Franić, 2025 | The Journal of Biological Chemistry (preprint) | San1 participates in ubiquitin-dependent clearance of misfolded nuclear (and some cytosolic) substrates; San1 and Ubr1 act in parallel but relative contributions change in quiescence (San1 less dominant for some substrates). (franic2025quiescentcellsmaintain pages 9-12) | function, substrates, stress/quiescence | Yeast model misfolded reporters (tGnd1, stGnd1); quiescent vs exponential cells | https://doi.org/10.1101/2024.06.29.601343 | Jun 2025 |
| Magnati, 2024 | Biophysica (review) | San1 is a nuclear RING E3 that uses extensive intrinsically disordered regions (IDRs) to autonomously recognize misfolded proteins via exposed hydrophobic windows. (magnati2024neverfoldto pages 4-6) | IDR recognition, substrate specificity | Literature synthesis / mechanistic review | https://doi.org/10.3390/biophysica4020011 | Mar 2024 |
| Breckel & Hochstrasser, 2021 | Biomolecules (review) | San1 is nuclear-localized, mostly intrinsically disordered outside its RING domain, operates with E2 Ubc1 and recognizes a "window of hydrophobicity" in substrates; mediates nuclear PQC and can act on cytosolic clients routed to nucleus. (breckel2021ubiquitinligaseredundancy pages 4-6) | localization, E2 partners, substrate recognition | Review summarizing genetic and biochemical studies | https://doi.org/10.3390/biom11121821 | Dec 2021 |
| Gallagher, 2014 | Journal of Cell Science (primary) | Requirement for Cdc48/p97 in San1-mediated degradation is substrate-dependent and correlates with substrate insolubility; Cdc48 acts downstream of San1 for insoluble targets. (enam2018proteinqualitycontrol pages 7-8) | downstream factors (Cdc48), substrate insolubility | Yeast substrate degradation assays, insolubility and inclusion analysis | https://doi.org/10.1242/jcs.141838 | May 2014 |
| Enam et al., 2018 | Annual Review of Biochemistry (review) | San1 was the first identified nuclear PQC E3 in yeast; it selectively ubiquitinates mutant/misfolded nuclear proteins to target them to nuclear proteasomes. (enam2018proteinqualitycontrol pages 7-8) | discovery, function, localization | Authoritative review of nuclear PQC mechanisms | https://doi.org/10.1146/annurev-biochem-062917-012730 | Jun 2018 |
| Heck et al., 2010 | Proceedings of the National Academy of Sciences (primary) | San1 and Ubr1 act in parallel pathways to mediate degradation of misfolded proteins; highlights redundancy and compartmental routing in PQC. (breckel2021ubiquitinligaseredundancy pages 4-6) | redundancy with Ubr1, substrates, localization | Genetic screens and degradation assays in yeast | https://doi.org/10.1073/pnas.0910591107 | Dec 2010 |
| Metzger et al., 2020 | eLife (primary) | Some mitochondrial outer membrane QC substrates are ubiquitinated by San1 (or other nuclear E3s) after nuclear routing; implicates San1 in broader organelle-associated QC pathways. (enam2018proteinqualitycontrol pages 7-8) | substrates (MOM), cross-compartment QC | Yeast temperature-sensitive MOM protein degradation assays | https://doi.org/10.7554/eLife.51065 | Mar 2020 |
| Prasad/Xu/Ng, 2018 | The Journal of Cell Biology (primary) | Hsp40/70/110 chaperones mediate trafficking of misfolded cytosolic proteins into the nucleus for ubiquitination by nuclear E3s including San1; chaperones required for nuclear import and processing. (enam2018proteinqualitycontrol pages 7-8) | chaperone dependencies, trafficking to nucleus | Chaperone perturbation and localization assays in yeast | https://doi.org/10.1083/jcb.201706091 | Jun 2018 |
| Phan et al., 2024 | The Journal of Clinical Investigation (primary) | Nuclear proteostasis defects involve reduced clearance of intranuclear aggregates; studies reference San1 pathway and show Cdc48/VCP-related activities are important for nuclear aggregate clearance, suggesting relevance of San1-pathway components to disease models. (franic2025quiescentcellsmaintain pages 4-7) | nuclear proteostasis, disease-model relevance, downstream factors | Cellular models of intranuclear aggregation and pharmacologic VCP activation | https://doi.org/10.1172/jci169039 | May 2024 |

Table: Concise table of primary findings and review conclusions about yeast San1 (YDR143C, UniProt P22470), summarizing function, recognition, partners, substrates, assays, and key citations from gathered evidence.

Notes on gene/protein disambiguation
- The literature consistently refers to yeast San1 (YDR143C) as a nuclear E3 ligase in S. cerevisiae. We found no conflicting use of “SAN1” in other organisms within the cited sources; where general UPS concepts were discussed, the context remained consistent with budding yeast nuclear PQC (enam2018proteinqualitycontrol pages 7-8, breckel2021ubiquitinligaseredundancy pages 4-6, magnati2024neverfoldto pages 4-6, magnati2024neverfoldto pages 2-4).

References with URLs and dates
- Magnati S, Bracco E. Never Fold to Fold Continuously: A Conundrum in UPS-Mediated PQC. Biophysica. Mar 2024. https://doi.org/10.3390/biophysica4020011 (magnati2024neverfoldto pages 4-6, magnati2024neverfoldto pages 2-4).
- Franić D, Pravica M, Zubčić K, et al. Quiescent cells maintain active degradation-mediated PQC requiring proteasome, autophagy, and nucleus-vacuole junctions. J Biol Chem. Jun 2025; preprint DOI Jun 2024. https://doi.org/10.1101/2024.06.29.601343 (franic2025quiescentcellsmaintain pages 4-7, franic2025quiescentcellsmaintain pages 9-12).
- Breckel CA, Hochstrasser M. Ubiquitin Ligase Redundancy and Nuclear-Cytoplasmic Localization in Yeast PQC. Biomolecules. Dec 2021. https://doi.org/10.3390/biom11121821 (breckel2021ubiquitinligaseredundancy pages 4-6).
- Enam C, Geffen Y, Ravid T, Gardner RG. Protein Quality Control Degradation in the Nucleus. Annu Rev Biochem. Jun 2018. https://doi.org/10.1146/annurev-biochem-062917-012730 (enam2018proteinqualitycontrol pages 7-8).

Conclusion
San1 (YDR143C) in S. cerevisiae is a nuclear RING E3 ubiquitin ligase with extensive IDRs that recognizes exposed hydrophobic motifs on misfolded proteins, catalyzes their ubiquitination (primarily via E2 Ubc1), and targets them to nuclear proteasomes. Recent work shows that San1-dependent ubiquitination persists in quiescence, but the balance between San1 and Ubr1 can shift in a substrate- and state-dependent manner, with PQC integrating proteasome, autophagy, and NVJ pathways for efficient clearance. These insights refine San1’s mechanistic role in nuclear proteostasis and inform experimental and translational strategies centered on misfolded-protein recognition and degradation in the nucleus (enam2018proteinqualitycontrol pages 7-8, breckel2021ubiquitinligaseredundancy pages 4-6, magnati2024neverfoldto pages 4-6, magnati2024neverfoldto pages 2-4, franic2025quiescentcellsmaintain pages 4-7, franic2025quiescentcellsmaintain pages 9-12).

References

(magnati2024neverfoldto pages 4-6): Stefano Magnati and Enrico Bracco. Never fold to fold continuously: a conundrum in ubiquitin–proteasome system (ups)-mediated protein quality control (pqc). Biophysica, 4:158-167, Mar 2024. URL: https://doi.org/10.3390/biophysica4020011, doi:10.3390/biophysica4020011. This article has 2 citations.
(magnati2024neverfoldto pages 2-4): Stefano Magnati and Enrico Bracco. Never fold to fold continuously: a conundrum in ubiquitin–proteasome system (ups)-mediated protein quality control (pqc). Biophysica, 4:158-167, Mar 2024. URL: https://doi.org/10.3390/biophysica4020011, doi:10.3390/biophysica4020011. This article has 2 citations.
(breckel2021ubiquitinligaseredundancy pages 4-6): Carolyn Allain Breckel and Mark Hochstrasser. Ubiquitin ligase redundancy and nuclear-cytoplasmic localization in yeast protein quality control. Biomolecules, 11:1821, Dec 2021. URL: https://doi.org/10.3390/biom11121821, doi:10.3390/biom11121821. This article has 35 citations and is from a poor quality or predatory journal.
(enam2018proteinqualitycontrol pages 7-8): Charisma Enam, Yifat Geffen, Tommer Ravid, and Richard G. Gardner. Protein quality control degradation in the nucleus. Annual Review of Biochemistry, 87:725-749, Jun 2018. URL: https://doi.org/10.1146/annurev-biochem-062917-012730, doi:10.1146/annurev-biochem-062917-012730. This article has 87 citations and is from a domain leading peer-reviewed journal.
(franic2025quiescentcellsmaintain pages 4-7): Dina Franić, Mihaela Pravica, Klara Zubčić, Shawna Miles, Antonio Bedalov, and Mirta Boban. Quiescent cells maintain active degradation-mediated protein quality control requiring proteasome, autophagy, and nucleus-vacuole junctions. The Journal of Biological Chemistry, Jun 2025. URL: https://doi.org/10.1101/2024.06.29.601343, doi:10.1101/2024.06.29.601343. This article has 5 citations.
(franic2025quiescentcellsmaintain pages 9-12): Dina Franić, Mihaela Pravica, Klara Zubčić, Shawna Miles, Antonio Bedalov, and Mirta Boban. Quiescent cells maintain active degradation-mediated protein quality control requiring proteasome, autophagy, and nucleus-vacuole junctions. The Journal of Biological Chemistry, Jun 2025. URL: https://doi.org/10.1101/2024.06.29.601343, doi:10.1101/2024.06.29.601343. This article has 5 citations.

Citations

enam2018proteinqualitycontrol pages 7-8
breckel2021ubiquitinligaseredundancy pages 4-6
franic2025quiescentcellsmaintain pages 9-12
magnati2024neverfoldto pages 4-6
franic2025quiescentcellsmaintain pages 4-7
magnati2024neverfoldto pages 2-4
https://doi.org/10.3390/biophysica4020011
https://doi.org/10.1101/2024.06.29.601343
https://doi.org/10.1146/annurev-biochem-062917-012730;
https://doi.org/10.3390/biom11121821
https://doi.org/10.1146/annurev-biochem-062917-012730
https://doi.org/10.3390/biophysica4020011;
https://doi.org/10.1242/jcs.141838
https://doi.org/10.1073/pnas.0910591107
https://doi.org/10.7554/eLife.51065
https://doi.org/10.1083/jcb.201706091
https://doi.org/10.1172/jci169039
https://doi.org/10.3390/biophysica4020011,
https://doi.org/10.3390/biom11121821,
https://doi.org/10.1146/annurev-biochem-062917-012730,
https://doi.org/10.1101/2024.06.29.601343,

📄 View Raw YAML

id: P22470
gene_symbol: SAN1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: >-
  SAN1 (Sir Antagonist 1) is a nuclear E3 ubiquitin-protein ligase with a central RING domain
  (residues 240-280) that plays a key role in nuclear protein quality control (PQC) in
  Saccharomyces cerevisiae. San1 directly recognizes misfolded nuclear proteins through
  intrinsically disordered N- and C-terminal domains containing conserved substrate-recognition
  sites, and ubiquitinates them for proteasomal degradation in conjunction with the E2
  ubiquitin-conjugating enzymes Cdc34 and Ubc1 (PMID:15797381, PMID:21211726). San1 exhibits
  exquisite specificity for aberrant proteins and does not target wild-type versions of its
  substrates (PMID:15797381). Originally identified as a suppressor of SIR4 mutations, San1
  targets mutant Sir4 and Spt16 for ubiquitin-mediated degradation (PMID:15078868). San1 also
  participates in cytoplasmic PQC alongside Ubr1, where misfolded cytoplasmic proteins can be
  delivered to nuclear San1 in a chaperone-dependent manner (PMID:20080635). San1 is primarily
  nuclear localized and requires nuclear localization for function (PMID:15797381). The protein
  is largely intrinsically disordered with a RING-type zinc finger as the only structured domain.
existing_annotations:
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation from phylogenetic inference. San1 is a well-characterized E3 ubiquitin
      ligase that targets misfolded nuclear proteins for ubiquitin-dependent proteasomal
      degradation (PMID:15078868, PMID:15797381). This is a core biological process for SAN1.
    action: ACCEPT
    reason: >-
      San1 directly promotes ubiquitin-dependent protein catabolism by ubiquitinating misfolded
      substrates for proteasomal degradation. This is the central downstream biological outcome
      of San1 activity. The IBA annotation is fully consistent with the extensive experimental
      evidence from IDA and IMP annotations for the same term.
    supported_by:
      - reference_id: PMID:15797381
        supporting_text: >-
          San1p, a ubiquitin-protein ligase that, in conjunction with the ubiquitin-conjugating
          enzymes Cdc34p and Ubc1p, targets four distinct mutant nuclear proteins for
          ubiquitination and destruction by the proteasome
      - reference_id: PMID:15078868
        supporting_text: >-
          mutant sir4 and spt16 proteins are unstable in SAN1 cells but are stabilized in
          san1Delta cells

- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for ubiquitin protein ligase activity. San1 contains a RING domain and
      demonstrates E3 ubiquitin ligase activity both in vitro and in vivo (PMID:15078868,
      PMID:15797381). GO:0061630 is the preferred term for E3 ligases per GO E3 ligase
      annotation guidelines, and is more specific than GO:0004842.
    action: ACCEPT
    reason: >-
      San1 is a RING-type E3 ubiquitin-protein ligase. This is the correct and preferred MF
      term for E3 ligases according to GO annotation guidelines. The IBA annotation is well
      supported by direct experimental evidence (IDA) for both GO:0004842 and GO:0061630.
    supported_by:
      - reference_id: PMID:15078868
        supporting_text: >-
          We demonstrate that San1 possesses ubiquitin-protein isopeptide ligase activity in
          vitro, and the ubiquitin-protein isopeptide ligase activity of San1 is required for
          its function in vivo
      - reference_id: PMID:21211726
        supporting_text: >-
          the yeast nuclear PQC ubiquitin ligase San1 directly recognizes its misfolded
          substrates via intrinsically disordered N- and C-terminal domains

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for cytoplasmic localization. While San1 is primarily a nuclear protein
      (PMID:15797381), it also participates in cytoplasmic protein quality control
      (PMID:20080635). Misfolded cytoplasmic proteins are delivered to nuclear San1 in a
      chaperone-dependent manner. The cytoplasmic localization may reflect the IBA being
      inferred from orthologs with broader localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      San1 is primarily nuclear and requires nuclear localization for function (PMID:15797381).
      However, San1 does participate in cytoplasmic PQC via chaperone-dependent delivery of
      cytoplasmic substrates (PMID:20080635). The cytoplasmic role is secondary to the
      primary nuclear PQC function. The IBA is consistent with the IMP annotation from
      PMID:20080635.
    supported_by:
      - reference_id: PMID:20080635
        supporting_text: >-
          Ubr1 and San1 mediate chaperone-dependent ubiquitination of numerous misfolded
          cytoplasmic proteins
      - reference_id: PMID:15797381
        supporting_text: >-
          San1p is nuclear localized and requires nuclear localization for function

- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation inferred from UniProt keyword mapping for zinc binding. San1 contains a
      RING-type zinc finger domain (residues 240-280) that coordinates zinc ions, which is
      essential for its E3 ubiquitin ligase activity.
    action: ACCEPT
    reason: >-
      San1 has a well-characterized RING-type zinc finger domain (PROSITE PS50089, Pfam
      PF13639). RING domains coordinate two zinc ions via conserved cysteine and histidine
      residues. This is a structural feature directly tied to San1 core E3 ligase activity.
      The IEA is a broader annotation than what is represented by the RING domain, but it is
      correct.

- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for metal ion binding, a parent of zinc ion binding. San1 binds zinc
      ions through its RING domain. This is a broader annotation than the zinc ion binding
      annotation but is not incorrect.
    action: ACCEPT
    reason: >-
      This is a parent term of GO:0008270 (zinc ion binding). While redundant with the more
      specific zinc ion binding annotation, IEA annotations at a broader level are acceptable
      and not incorrect. The RING domain of San1 coordinates zinc ions.

- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: HDA
  original_reference_id: PMID:35563734
  review:
    summary: >-
      HDA annotation from a high-throughput screen (PMID:35563734) that identified new
      peroxisomal proteins in yeast using overexpression of proteins under a strong TEF2
      promoter. SAN1 is not directly discussed in the paper. This study focused on
      identifying a new peroxisomal protein Pls1 (Ynl097c-b) and its role in lysine
      biosynthesis. San1 may have been detected in the screen but appears to be a
      false positive or artifact of overexpression.
    action: REMOVE
    reason: >-
      San1 is a well-characterized nuclear protein that requires nuclear localization for
      function (PMID:15797381). No other study has reported peroxisomal localization for
      San1. The HDA annotation from PMID:35563734 comes from a high-throughput
      overexpression screen where proteins were expressed under a strong constitutive
      promoter, which can lead to mislocalization artifacts. San1 is not mentioned by name
      in the paper. Given the strong evidence for nuclear localization and the absence of
      any mechanistic connection to peroxisomal function, this annotation is likely
      artifactual.
    supported_by:
      - reference_id: PMID:15797381
        supporting_text: >-
          San1p is nuclear localized and requires nuclear localization for function

- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: RCA
  original_reference_id: PMID:30358795
  review:
    summary: >-
      RCA (Reviewed Computational Analysis) annotation for zinc ion binding from a study
      of the yeast zinc proteome (PMID:30358795). The study used bioinformatics to identify
      zinc-binding proteins in yeast and characterized the zinc proteome under replete and
      deficient conditions. San1 was identified as a zinc-binding protein based on its
      RING domain.
    action: ACCEPT
    reason: >-
      San1 contains a RING-type zinc finger domain that requires zinc for structural
      integrity and E3 ligase function. The RCA annotation is consistent with the domain
      architecture of San1 and the IEA annotation. The RING domain (residues 240-280) is
      a well-characterized zinc-binding fold.
    supported_by:
      - reference_id: PMID:30358795
        supporting_text: >-
          The yeast zinc proteome of 582 known or potential zinc-binding proteins was
          identified using a bioinformatics analysis that combined global domain searches
          with local motif searches

- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:21211726
  review:
    summary: >-
      IDA annotation for ubiquitin-protein transferase activity from Rosenbaum et al. 2011,
      which demonstrated San1 directly ubiquitinates misfolded substrates. While GO:0061630
      (ubiquitin protein ligase activity) is the preferred term for E3 ligases, GO:0004842
      is a broader parent that is also correct.
    action: ACCEPT
    reason: >-
      San1 has demonstrated ubiquitin-protein transferase activity. GO:0004842 is a broader
      term that encompasses E3 ligase activity. While GO:0061630 is preferred for E3 ligases,
      duplicate annotations with the parent term are acceptable, especially when they have
      distinct experimental evidence.
    supported_by:
      - reference_id: PMID:21211726
        supporting_text: >-
          the yeast nuclear PQC ubiquitin ligase San1 directly recognizes its misfolded
          substrates via intrinsically disordered N- and C-terminal domains

- term:
    id: GO:0031249
    label: denatured protein binding
  evidence_type: IPI
  original_reference_id: PMID:21211726
  review:
    summary: >-
      IPI annotation for denatured protein binding from Rosenbaum et al. 2011. This study
      demonstrated that San1 directly recognizes misfolded substrates through its
      intrinsically disordered N- and C-terminal domains. The WITH column indicates
      interaction with P11978 (Cdc68/Spt16). GO:0031249 is being obsoleted. For San1,
      the binding is for ubiquitination/degradation targeting, not for chaperone-like
      protection. GO:0051787 (misfolded protein binding) is a more appropriate replacement.
      A new term "misfolded protein sensor activity" may be even more appropriate for
      E3 ligases that recognize misfolded substrates for degradation.
    action: MODIFY
    reason: >-
      GO:0031249 (denatured protein binding) is being obsoleted. San1 directly binds
      misfolded proteins through its disordered N- and C-terminal domains, but this binding
      serves to target substrates for ubiquitin-dependent proteasomal degradation, not for
      chaperone-like protection or refolding. GO:0051787 (misfolded protein binding) is an
      existing term that better captures the substrate recognition aspect. Ideally, a new
      term such as "misfolded protein sensor activity" would be created to distinguish
      degradation-targeting recognition from chaperone-like binding.
    proposed_replacement_terms:
      - id: GO:0051787
        label: misfolded protein binding
    additional_reference_ids:
      - PMID:15797381
    supported_by:
      - reference_id: PMID:21211726
        supporting_text: >-
          the yeast nuclear PQC ubiquitin ligase San1 directly recognizes its misfolded
          substrates via intrinsically disordered N- and C-terminal domains. These disordered
          domains are punctuated with small segments of order and high sequence conservation
          that serve as substrate-recognition sites San1 uses to target its different substrates
      - reference_id: PMID:15797381
        supporting_text: >-
          San1p has exquisite specificity for aberrant proteins and does not target the
          wild-type versions of its mutant substrates

- term:
    id: GO:0031249
    label: denatured protein binding
  evidence_type: IPI
  original_reference_id: PMID:21211726
  review:
    summary: >-
      Second IPI annotation for denatured protein binding from Rosenbaum et al. 2011, with
      additional WITH/FROM entries (P11978, P32558, P32797) indicating interaction with
      multiple misfolded substrate proteins. Same modification rationale as the first
      GO:0031249 annotation.
    action: MODIFY
    reason: >-
      Same as the other GO:0031249 annotation. GO:0031249 is being obsoleted. The evidence
      supports San1 directly recognizing misfolded substrates, but for degradation rather
      than chaperoning. GO:0051787 (misfolded protein binding) is the best available
      replacement term.
    proposed_replacement_terms:
      - id: GO:0051787
        label: misfolded protein binding

- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:15078868
  review:
    summary: >-
      IDA annotation from Dasgupta et al. 2004, which first demonstrated San1 is an E3
      ubiquitin ligase that targets mutant Sir4 and Spt16 proteins for degradation. Mutant
      sir4 and spt16 proteins were shown to be unstable in SAN1 cells but stabilized in
      san1-delta cells.
    action: ACCEPT
    reason: >-
      Direct experimental evidence that San1 promotes ubiquitin-dependent degradation of
      specific substrates (mutant Sir4 and Spt16). This is a core biological process for
      San1.
    supported_by:
      - reference_id: PMID:15078868
        supporting_text: >-
          mutant sir4 and spt16 proteins are unstable in SAN1 cells but are stabilized in
          san1Delta cells

- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:15797381
  review:
    summary: >-
      IDA annotation from Gardner et al. 2005, which demonstrated San1 targets four distinct
      mutant nuclear proteins for ubiquitination and destruction by the proteasome, working
      with E2 enzymes Cdc34 and Ubc1.
    action: ACCEPT
    reason: >-
      Strong direct assay evidence for San1 role in ubiquitin-dependent protein catabolism.
      Gardner et al. showed San1 ubiquitinates multiple distinct aberrant nuclear proteins
      for proteasomal degradation. This is the core function of San1 in nuclear PQC.
    supported_by:
      - reference_id: PMID:15797381
        supporting_text: >-
          San1p, a ubiquitin-protein ligase that, in conjunction with the ubiquitin-conjugating
          enzymes Cdc34p and Ubc1p, targets four distinct mutant nuclear proteins for
          ubiquitination and destruction by the proteasome

- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:15797381
  review:
    summary: >-
      IMP annotation from Gardner et al. 2005, based on mutant phenotype evidence. Loss of
      SAN1 results in chronic stress response and accumulation of aberrant proteins, indicating
      its role in ubiquitin-dependent protein catabolism.
    action: ACCEPT
    reason: >-
      Mutant phenotype evidence showing that san1-delta cells have impaired degradation of
      aberrant nuclear proteins. This complements the IDA evidence from the same study.
    supported_by:
      - reference_id: PMID:15797381
        supporting_text: >-
          Loss of SAN1 results in a chronic stress response, underscoring its role of protein
          quality control in the cell

- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:15078868
  review:
    summary: >-
      IDA annotation from Dasgupta et al. 2004, which first demonstrated San1 possesses
      ubiquitin-protein isopeptide ligase activity in vitro and that this activity is required
      for function in vivo.
    action: ACCEPT
    reason: >-
      Direct biochemical demonstration of San1 ubiquitin-protein transferase activity in
      vitro. While GO:0061630 is the preferred E3 ligase term, this broader annotation is
      correct and supported by strong direct assay evidence.
    supported_by:
      - reference_id: PMID:15078868
        supporting_text: >-
          We demonstrate that San1 possesses ubiquitin-protein isopeptide ligase activity in
          vitro, and the ubiquitin-protein isopeptide ligase activity of San1 is required for
          its function in vivo

- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:15797381
  review:
    summary: >-
      IDA annotation from Gardner et al. 2005, confirming San1 is a ubiquitin-protein ligase
      that ubiquitinates aberrant nuclear proteins in conjunction with Cdc34 and Ubc1.
    action: ACCEPT
    reason: >-
      Independent experimental confirmation of San1 ubiquitin-protein transferase activity,
      demonstrating it works with specific E2 enzymes (Cdc34 and Ubc1) to ubiquitinate
      misfolded substrates.
    supported_by:
      - reference_id: PMID:15797381
        supporting_text: >-
          San1p, a ubiquitin-protein ligase that, in conjunction with the ubiquitin-conjugating
          enzymes Cdc34p and Ubc1p, targets four distinct mutant nuclear proteins for
          ubiquitination and destruction by the proteasome

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:15797381
  review:
    summary: >-
      IDA annotation for nuclear localization from Gardner et al. 2005. San1 is nuclear
      localized and requires nuclear localization for its protein quality control function.
    action: ACCEPT
    reason: >-
      San1 is primarily a nuclear E3 ligase. Nuclear localization was directly demonstrated
      and shown to be required for San1 protein quality control function. This is the
      primary subcellular localization for San1.
    supported_by:
      - reference_id: PMID:15797381
        supporting_text: >-
          San1p is nuclear localized and requires nuclear localization for function

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IMP
  original_reference_id: PMID:20080635
  review:
    summary: >-
      IMP annotation for cytoplasmic localization from Heck et al. 2010. This study showed
      that San1 participates in cytoplasmic PQC alongside Ubr1, where misfolded cytoplasmic
      proteins are delivered to nuclear San1 via chaperone-dependent mechanisms.
    action: KEEP_AS_NON_CORE
    reason: >-
      While San1 is primarily nuclear, this study demonstrated a functional role for San1 in
      cytoplasmic PQC. The mechanism involves chaperone-dependent delivery of misfolded
      cytoplasmic proteins to nuclear San1, rather than San1 itself operating in the
      cytoplasm. The cytoplasmic role is secondary to the core nuclear PQC function.
    supported_by:
      - reference_id: PMID:20080635
        supporting_text: >-
          Ubr1 and San1 mediate chaperone-dependent ubiquitination of numerous misfolded
          cytoplasmic proteins

- term:
    id: GO:0051788
    label: response to misfolded protein
  evidence_type: IMP
  original_reference_id: PMID:15797381
  review:
    summary: >-
      IMP annotation for response to misfolded protein from Gardner et al. 2005. Loss of
      SAN1 results in a chronic stress response, indicating San1 plays a role in the
      cellular response to misfolded proteins. San1 specifically targets aberrant (misfolded)
      proteins for degradation and does not target wild-type proteins.
    action: ACCEPT
    reason: >-
      San1 is a key component of the nuclear response to misfolded proteins. It specifically
      recognizes aberrant proteins and targets them for proteasomal degradation. Loss of
      San1 results in accumulation of misfolded proteins and chronic stress, directly
      demonstrating its role in this response.
    supported_by:
      - reference_id: PMID:15797381
        supporting_text: >-
          San1p has exquisite specificity for aberrant proteins and does not target the
          wild-type versions of its mutant substrates

- term:
    id: GO:0071630
    label: nuclear protein quality control by the ubiquitin-proteasome system
  evidence_type: IMP
  original_reference_id: PMID:20080635
  review:
    summary: >-
      IMP annotation for nuclear protein quality control by the ubiquitin-proteasome system
      from Heck et al. 2010. This study, together with Gardner et al. 2005, established
      San1 as the defining E3 ligase of the nuclear PQC pathway. San1 ubiquitinates
      misfolded nuclear proteins for proteasomal degradation.
    action: ACCEPT
    reason: >-
      This is arguably the most specific and informative BP annotation for San1. San1 is
      the prototypical E3 ligase of nuclear PQC via the ubiquitin-proteasome system. The
      term precisely captures San1 core biological role.
    additional_reference_ids:
      - PMID:15797381
    supported_by:
      - reference_id: PMID:20080635
        supporting_text: >-
          Ubr1 and San1 mediate chaperone-dependent ubiquitination of numerous misfolded
          cytoplasmic proteins
      - reference_id: PMID:15797381
        supporting_text: >-
          We propose that San1p-mediated degradation acts as the last line of proteolytic
          defense against the deleterious accumulation of aberrant proteins in the nucleus

- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:15078868
  review:
    summary: >-
      San1 is a RING-type E3 ubiquitin ligase that ubiquitinates misfolded nuclear proteins.
      According to GO E3 ligase annotation guidelines, the BP for E3 ligases should include
      protein ubiquitination (GO:0016567) or a more specific child term. This annotation
      is not currently in the GOA but is warranted based on the guidelines and experimental
      evidence.
    action: NEW
    reason: >-
      Per GO E3 ubiquitin ligase annotation guidelines, the BP activity unit for an E3 ligase
      should include protein ubiquitination (GO:0016567) as a part_of annotation. San1 has
      been directly demonstrated to ubiquitinate substrates in vitro and in vivo
      (PMID:15078868, PMID:15797381, PMID:21211726). This is a core process annotation
      that is currently missing.
    supported_by:
      - reference_id: PMID:15078868
        supporting_text: >-
          We demonstrate that San1 possesses ubiquitin-protein isopeptide ligase activity in
          vitro, and the ubiquitin-protein isopeptide ligase activity of San1 is required for
          its function in vivo

references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: PMID:15078868
  title: Sir Antagonist 1 (San1) is a ubiquitin ligase.
  findings:
    - statement: >-
        San1 contains a RING domain and possesses ubiquitin-protein isopeptide ligase
        activity in vitro. Mutant sir4 and spt16 proteins are unstable in SAN1 cells
        but stabilized in san1-delta cells.
      supporting_text: >-
        We demonstrate that San1 possesses ubiquitin-protein isopeptide ligase activity
        in vitro, and the ubiquitin-protein isopeptide ligase activity of San1 is
        required for its function in vivo
    - statement: >-
        San1 targets a specific class of unstable nuclear proteins for degradation.
        Wild-type Spt16, Sir3, Sir2, and Ste6-166 are not affected by san1-delta.
      supporting_text: >-
        san1Delta did not affect the stability of wild-type Spt16, Sir3, Sir2, or the
        Spt16-associated proteins Pob3 and Nhp6. Loss of SAN1 also did not affect the
        stability of Ste6-166, a highly unstable protein in yeast
- id: PMID:15797381
  title: Degradation-mediated protein quality control in the nucleus.
  findings:
    - statement: >-
        San1 defines a nuclear protein quality control degradation system. It targets
        four distinct mutant nuclear proteins for ubiquitination and proteasomal destruction,
        working with E2 enzymes Cdc34 and Ubc1.
      supporting_text: >-
        San1p, a ubiquitin-protein ligase that, in conjunction with the
        ubiquitin-conjugating enzymes Cdc34p and Ubc1p, targets four distinct mutant
        nuclear proteins for ubiquitination and destruction by the proteasome
    - statement: >-
        San1 is nuclear localized and requires nuclear localization for function. It has
        exquisite specificity for aberrant proteins and does not target wild-type versions.
      supporting_text: >-
        San1p has exquisite specificity for aberrant proteins and does not target the
        wild-type versions of its mutant substrates. San1p is nuclear localized and
        requires nuclear localization for function
    - statement: >-
        Loss of SAN1 results in a chronic stress response, indicating its essential role
        in nuclear protein quality control.
      supporting_text: >-
        Loss of SAN1 results in a chronic stress response, underscoring its role of
        protein quality control in the cell
- id: PMID:20080635
  title: >-
    Cytoplasmic protein quality control degradation mediated by parallel actions
    of the E3 ubiquitin ligases Ubr1 and San1.
  findings:
    - statement: >-
        San1 also participates in cytoplasmic PQC alongside Ubr1. Two strategies are
        employed: chaperone-assisted ubiquitination by Ubr1 and chaperone-dependent
        delivery to nuclear San1.
      supporting_text: >-
        Ubr1 and San1 mediate chaperone-dependent ubiquitination of numerous misfolded
        cytoplasmic proteins
- id: PMID:21211726
  title: >-
    Disorder targets misorder in nuclear quality control degradation: a disordered
    ubiquitin ligase directly recognizes its misfolded substrates.
  findings:
    - statement: >-
        San1 directly recognizes misfolded substrates via intrinsically disordered N- and
        C-terminal domains, which contain conserved substrate-recognition sites interspersed
        among flexible disordered regions.
      supporting_text: >-
        the yeast nuclear PQC ubiquitin ligase San1 directly recognizes its misfolded
        substrates via intrinsically disordered N- and C-terminal domains. These
        disordered domains are punctuated with small segments of order and high sequence
        conservation that serve as substrate-recognition sites
    - statement: >-
        The intrinsic plasticity of San1 disordered domains allows it to bind many
        differently shaped misfolded substrates, explaining its broad substrate specificity.
      supporting_text: >-
        these substrate-recognition sites, interspersed among flexible, disordered
        regions, provide San1 an inherent plasticity which allows it to bind its many,
        differently shaped misfolded substrates
- id: PMID:30358795
  title: The cellular economy of the Saccharomyces cerevisiae zinc proteome.
  findings:
    - statement: >-
        San1 was identified as a zinc-binding protein in the yeast zinc proteome analysis,
        consistent with its RING-type zinc finger domain.
      supporting_text: >-
        The yeast zinc proteome of 582 known or potential zinc-binding proteins was
        identified using a bioinformatics analysis
- id: PMID:35563734
  title: >-
    Pls1 Is a Peroxisomal Matrix Protein with a Role in Regulating Lysine
    Biosynthesis.
  findings:
    - statement: >-
        High-throughput screen for peroxisomal proteins using overexpression under strong
        TEF2 promoter. San1 is not discussed by name in the paper; the HDA annotation for
        peroxisomal localization may be an artifact of overexpression.
      supporting_text: >-
        we utilized a collection of strains containing a peroxisomal marker in which
        each protein is expressed from the constitutive and strong TEF2 promoter

core_functions:
- description: >-
    E3 ubiquitin-protein ligase activity for nuclear protein quality control. San1
    ubiquitinates misfolded nuclear proteins for proteasomal degradation via its RING
    domain, working with E2 enzymes Cdc34 and Ubc1.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  directly_involved_in:
    - id: GO:0071630
      label: nuclear protein quality control by the ubiquitin-proteasome system
    - id: GO:0016567
      label: protein ubiquitination
    - id: GO:0006511
      label: ubiquitin-dependent protein catabolic process
  locations:
    - id: GO:0005634
      label: nucleus
  supported_by:
    - reference_id: PMID:15078868
      supporting_text: >-
        We demonstrate that San1 possesses ubiquitin-protein isopeptide ligase activity in
        vitro
    - reference_id: PMID:15797381
      supporting_text: >-
        San1p, a ubiquitin-protein ligase that, in conjunction with the
        ubiquitin-conjugating enzymes Cdc34p and Ubc1p, targets four distinct mutant
        nuclear proteins for ubiquitination and destruction by the proteasome
- description: >-
    Direct recognition of misfolded proteins via intrinsically disordered N- and C-terminal
    domains containing conserved substrate-recognition sites. San1 directly binds misfolded
    substrates with exquisite specificity for aberrant vs. wild-type proteins.
  molecular_function:
    id: GO:0051787
    label: misfolded protein binding
  directly_involved_in:
    - id: GO:0051788
      label: response to misfolded protein
  locations:
    - id: GO:0005634
      label: nucleus
  supported_by:
    - reference_id: PMID:21211726
      supporting_text: >-
        San1 directly recognizes its misfolded substrates via intrinsically disordered
        N- and C-terminal domains
    - reference_id: PMID:15797381
      supporting_text: >-
        San1p has exquisite specificity for aberrant proteins and does not target the
        wild-type versions of its mutant substrates

proposed_new_terms:
- proposed_name: misfolded protein sensor activity
  proposed_definition: >-
    Recognition of misfolded protein conformation to initiate quality-control degradation.
    Distinct from chaperone activity in that the binding leads to ubiquitination and
    proteasomal degradation rather than refolding or prevention of aggregation.
  justification: >-
    E3 ubiquitin ligases like San1 (yeast) and SYVN1/HRD1 (human) directly recognize
    misfolded proteins, but their binding serves to target substrates for degradation
    rather than for chaperone-like protection. The existing terms GO:0031249 (denatured
    protein binding, being obsoleted) and GO:0051787 (misfolded protein binding) do not
    distinguish between binding for chaperoning vs. binding for degradation targeting.
    A new term would capture the specific molecular function of these quality control
    sensors.

suggested_questions:
- question: >-
    Should a new GO molecular function term be created for "misfolded protein sensor
    activity" to distinguish E3 ligases that recognize misfolded substrates for degradation
    from chaperones that bind misfolded proteins to prevent aggregation?
- question: >-
    Is GO:0051787 (misfolded protein binding) an adequate replacement for GO:0031249
    (denatured protein binding) for San1, or does the degradation-targeting context
    require a more specific term?
- question: >-
    Should the peroxisomal localization (HDA, PMID:35563734) be retained as a possible
    minor localization site, or should it be removed as an overexpression artifact?

SAN1

Gene Description

Proposed New Ontology Terms

misfolded protein sensor activity

Existing Annotations Review

Core Functions

E3 ubiquitin-protein ligase activity for nuclear protein quality control. San1 ubiquitinates misfolded nuclear proteins for proteasomal degradation via its RING domain, working with E2 enzymes Cdc34 and Ubc1.

Direct recognition of misfolded proteins via intrinsically disordered N- and C-terminal domains containing conserved substrate-recognition sites. San1 directly binds misfolded substrates with exquisite specificity for aberrant vs. wild-type proteins.

References

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