TOR1 GO Annotation Curation Summary

Overview

Comprehensive curation review of 79 GO annotations for yeast TOR1 (P35169), the serine/threonine kinase and core component of TORC1 complex.

Curation Statistics

Category	Count	Action	Rationale
MOLECULAR FUNCTIONS
Kinase catalytic activity	5	ACCEPT	GO:0004674 (IBA, IDA x3), GO:0004672 (EXP, IMP), GO:0106310 (IEA). Core function.
Nucleotide/ATP binding	3	ACCEPT	GO:0000166, GO:0005524, GO:0016301. Essential cofactor binding for kinase.
Transferase activity	1	ACCEPT	GO:0016740. Phosphoryl transfer mechanism.
Complex binding	1	ACCEPT	GO:0044877. FRB domain mediates FKBP-rapamycin binding.
Protein binding (generic)	15	MARK_AS_OVER_ANNOTATED	Generic GO:0005515 from multiple IPI sources redundant with GO:0031931 (TORC1 complex) and GO:0044877 (complex binding)
CELLULAR COMPONENTS
Nucleus	2	ACCEPT	GO:0005634 (IBA, IDA). TOR1 translocates to nucleus for rDNA transcription control.
Cytoplasm	3	ACCEPT	GO:0005737 (IBA, IDA x2). Core subcellular location.
Vacuolar membrane	5	ACCEPT	GO:0000329 (IEA, IDA x4, HDA). Critical for TORC1 nutrient sensing.
Plasma membrane	2	ACCEPT	GO:0005886 (IEA, IDA). TOR1 peripheral membrane protein.
Vacuole membrane	1	ACCEPT	GO:0005774 (IEA). Parent term to fungal-type vacuole.
Golgi membrane	1	ACCEPT	GO:0000139 (IDA). TOR1 localizes to multiple membrane compartments.
Endosome membrane	1	ACCEPT	GO:0010008 (IDA). Nutrient sensing from endosomal compartments.
COMPLEX MEMBERSHIP
TOR complex	1	ACCEPT	GO:0038201 (IBA). TOR1 core component.
TORC1 complex	2	ACCEPT	GO:0031931 (IEA, IPI). Core TORC1 component (TOR1, KOG1, LST8, TCO89).
BIOLOGICAL PROCESSES
TORC1/TOR signaling	5	ACCEPT	GO:0038202 (IBA), GO:0031929 (IEA, NAS, IMP x2). Core pathway.
Nutrient response	1	ACCEPT	GO:0007584 (NAS). TOR1 master nutrient sensor.
Nitrogen starvation response	2	ACCEPT	GO:0006995 (IEA, IGI). TORC1 controls autophagy/anabolic responses to N-availability.
Autophagy inhibition	3	ACCEPT	GO:0016242 (IBA), GO:0010507 (IEA, IGI). Core TORC1 output.
Translation initiation	1	ACCEPT	GO:0006413 (IMP). TOR loss blocks translation initiation.
Ribosome biogenesis	2	ACCEPT	GO:0042254 (IEA, IMP). Major TORC1 function (rRNA synthesis, r-protein transcription).
rRNA transcription	1	ACCEPT	GO:0042790 (IMP). TOR1 nuclear localization regulates rDNA.
S6 phosphorylation	1	ACCEPT	GO:0018105 (IDA). Major translation control output via ribosomal protein S6.
Cell growth regulation	1	ACCEPT	GO:0001558 (NAS). Master regulator of growth.
Cell cycle regulation	2	ACCEPT	GO:0051726 (NAS, IMP). Controls G1/S progression.
Meiotic cell cycle	1	ACCEPT	GO:0051321 (IMP). TOR kinase activity required for meiosis.
STRESS RESPONSES	3-4	KEEP_AS_NON_CORE	GO:0034976, GO:0034599, GO:0034605, GO:0006974. Peripheral to primary nutrient sensing.
BIOSYNTHETIC PROCESSES	3	KEEP_AS_NON_CORE	GO:0031505 (cell wall), GO:0090153 (sphingolipids), GO:1905356 (snRNA modification). Downstream outputs.
MITOCHONDRIAL SIGNALING	1	KEEP_AS_NON_CORE	GO:0031930 (RTG retrograde). Specific nutrient-dependent output.

Detailed Curation Decisions

ACCEPT Annotations (60 annotations)

Molecular Functions - Kinase Activity

All kinase activity annotations should be accepted as they represent core function:
- GO:0004674 (protein serine/threonine kinase activity): IBA, IEA, IDA(3)
- Core activity with EC 2.7.11.1 confirmation in UniProt
- Experimental evidence from PMID:38127619, PMID:36691768, PMID:26582391

GO:0004672 (protein kinase activity): EXP, IMP
EXP from PMID:18270585
IMP from Tap42 phosphorylation (PMID:10329624)
GO:0106310 (protein serine kinase activity): IEA
Rhea-based mapping for serine-specific phosphorylation

All kinase related terms are core functions.

Nucleotide and Cofactor Binding

GO:0000166 (nucleotide binding): IEA
GO:0005524 (ATP binding): IEA
GO:0016301 (kinase activity): IEA
GO:0016740 (transferase activity): IEA

These are essential for kinase function and should be accepted.

Cellular Localization

Nucleus - ACCEPT
- GO:0005634: IBA, IDA(2)
- Evidence: PMID:16900101 demonstrates nuclear translocation and rDNA association in response to nutrients
- Function: Nuclear localization required for ribosomal protein gene transcription control

Cytoplasm - ACCEPT
- GO:0005737: IBA, IDA(2)
- Evidence: Multiple observations of cytoplasmic TOR1 localization
- Function: Primary site of TORC1 complex assembly and signaling

Vacuolar Membrane - ACCEPT
- GO:0000329: IEA, IDA(4), HDA
- Evidence: PMID:25046117, PMID:19748353, PMID:18723607, PMID:12719473
- Function: Critical site for amino acid sensing via EGO complex and PIB2 glutamine sensor

Plasma Membrane - ACCEPT
- GO:0005886: IEA, IDA
- Evidence: PMID:10973982 shows TOR2 (TOR1-related) plasma membrane localization via HEAT repeats
- Function: TORC1 can sense growth factors at plasma membrane

Other Compartments - ACCEPT
- GO:0005774 (vacuolar membrane): IEA - parent term
- GO:0000139 (Golgi membrane): IDA - nutrient sensing from multiple compartments
- GO:0010008 (endosome membrane): IDA - endosomal nutrient sensing

TORC1 Complex Membership - ACCEPT

GO:0038201 (TOR complex): IBA
GO:0031931 (TORC1 complex): IEA, IPI (PMID:12408816)

Evidence: PMID:12408816 seminal paper identifying TORC1 composition: TOR1/TOR2 + KOG1 + LST8 [+ TCO89]

Major Biological Processes - ACCEPT

TORC1/TOR Signaling - ACCEPT (multiple annotations, all core)
- GO:0038202 (TORC1 signaling): IBA
- GO:0031929 (TOR signaling): IEA, NAS, IMP(2)
- These are the primary pathway controlled by TOR1

Nutrient Sensing - ACCEPT
- GO:0006995 (cellular response to nitrogen starvation): IEA, IGI
- GO:0007584 (response to nutrient): NAS
- Evidence: PMID:9461583 - foundational autophagy control paper
- TOR1 acts as nutrient availability sensor

Autophagy Regulation - ACCEPT (core function)
- GO:0016242 (negative regulation of macroautophagy): IBA
- GO:0010507 (negative regulation of autophagy): IEA, IGI
- Evidence: PMID:9461583 classic paper demonstrating TOR inhibits autophagy
- Under nutrient-rich conditions, TORC1 suppresses autophagy

Protein Synthesis Regulation - ACCEPT
- GO:0006413 (translational initiation): IMP (PMID:8741837)
- Evidence: TOR loss causes block of translation initiation
- GO:0042254 (ribosome biogenesis): IEA, IMP (PMID:10198052)
- Evidence: PMID:10198052 demonstrates TOR controls rRNA transcription, r-protein gene expression, rRNA processing
- GO:0042790 (nucleolar large rRNA transcription): IMP (PMID:16900101)
- Evidence: TOR1 translocates to nucleus and associates with rDNA promoters
- GO:0018105 (peptidyl-serine phosphorylation): IDA (PMID:26582391)
- Evidence: Direct phosphorylation of ribosomal protein S6

Cell Growth and Cycle Control - ACCEPT
- GO:0001558 (regulation of cell growth): NAS
- GO:0051726 (regulation of cell cycle): NAS, IMP (PMID:8741837)
- GO:0051321 (meiotic cell cycle): IMP (PMID:9096347)
- Evidence: TOR depletion arrests cells in G1; rapamycin similarly blocks growth
- TOR kinase activity required for meiotic progression

KEEP_AS_NON_CORE Annotations (7-8 annotations)

These annotations are likely correct but represent peripheral functions rather than core TOR1 roles:

Stress Responses
- GO:0034976 (response to ER stress): IMP (PMID:31144305)
- Hyperactive TORC1 sensitizes to ER stress
- Reason: TOR is sensor, but ER stress response is secondary

GO:0034599 (cellular response to oxidative stress): IGI (PMID:27922823)
GO:0034605 (cellular response to heat): IGI (PMID:27922823)
Via Slm35-TOR-longevity link
Reason: Peripheral stress adaptation via TOR, not primary function
GO:0006974 (DNA damage response): IMP (PMID:17698581)
TOR as survival checkpoint
Reason: Secondary to primary nutrient sensing

Biosynthetic Processes
- GO:0031505 (fungal-type cell wall organization): IMP (PMID:14736892)
- TORC1 controls cell wall integrity via Ssd1p
- Reason: Downstream anabolic output, not core function

GO:0090153 (regulation of sphingolipid biosynthesis): IMP (PMID:23363605)
TORC1 phosphorylates Npr1, which phosphorylates Orm
Reason: Specific lipid biosynthesis output of nutrient sensing
GO:1905356 (regulation of snRNA pseudouridine synthesis): IEA, IGI
TOR-dependent ribosome biogenesis output
Reason: Specific ribosomal modification, consequence not core driver

Retrograde Signaling
- GO:0031930 (mitochondria-nucleus signaling pathway): IMP (PMID:11997479)
- TOR controls RTG1/RTG3 nuclear localization
- Reason: Specific downstream output of amino acid sensing

MARK_AS_OVER_ANNOTATED Annotations (15 annotations)

Generic "Protein Binding" Annotations (GO:0005515)

All IPI annotations for generic GO:0005515 should be marked as over-annotated:

From IntAct database with PMIDs:
- PMID:12408816: FPR1, KOG1, LST8
- PMID:14736892: KOG1, LST8, TCO89
- PMID:16429126: (generic interaction screen)
- PMID:16554755: (generic interaction screen)
- PMID:18812505: FPR1 (superoxide-TORC1 interaction)
- PMID:20489023: multiple partners (NPR1, MKS1, KSP1, NNK1, FMP48, SKY1, TCO89)

Rationale for Over-Annotation:

GO Curation Best Practices: Generic "protein binding" (GO:0005515) is discouraged because it is uninformative without mechanistic detail.
Redundancy with Existing Annotations:
TORC1 complex membership is captured by: GO:0031931 (TORC1 complex, part_of relation)
FKBP-rapamycin binding is captured by: GO:0044877 (protein-containing complex binding, enables relation)
Information Loss: Multiple partner-specific IPI annotations collapse into single generic term. Better to use:
GO:0031931 (TORC1 complex) for core complex members (KOG1, LST8, TCO89)
GO:0044877 (protein-containing complex binding) for FBP-rapamycin interaction
Or define more specific MF terms if available (e.g., "rapamycin-binding activity")
Solution: Consolidate these 15 IPI/GO:0005515 annotations. Retain the more informative:
GO:0031931 (TORC1 complex): captures core component interactions
GO:0044877 (protein-containing complex binding): captures FKBP interaction

Conclusion: The 15 generic protein binding annotations should be marked as OVER_ANNOTATED and consolidated into more specific functional annotations already present.

Summary by Evidence Code Quality

Evidence	Count	Quality	Retention
IBA	~10	High (phylogenetic)	ACCEPT
IDA	~20	High (direct observation)	ACCEPT
IMP	~20	High (mutant phenotype)	ACCEPT/NON-CORE
IGI	~8	Medium-High (genetic interaction)	ACCEPT/NON-CORE
IPI	~15	Medium (interaction)	MARK_AS_OVER_ANNOTATED
IEA	~12	Medium (electronic)	ACCEPT
EXP	1	High (experimental)	ACCEPT
NAS	4	Low (non-traceable)	ACCEPT
HDA	1	Low (homology)	ACCEPT

Core Functions Summary

Primary Functions (ACCEPT - absolutely essential):
1. Serine/threonine kinase activity (GO:0004674)
2. ATP binding (GO:0005524)
3. TORC1 complex membership (GO:0031931)
4. TORC1 signaling pathway (GO:0038202)
5. Negative regulation of autophagy (GO:0016242, GO:0010507)
6. Ribosome biogenesis control (GO:0042254)
7. Translation initiation control (GO:0006413)
8. Nutrient sensing (GO:0007584, GO:0006995)
9. Cell growth regulation (GO:0001558)
10. Cell cycle regulation (GO:0051726)

Supporting Localizations (ACCEPT):
- Vacuolar membrane (GO:0000329) - nutrient sensing
- Nucleus (GO:0005634) - rDNA transcription
- Cytoplasm (GO:0005737) - signaling hub
- Plasma membrane (GO:0005886) - growth factor sensing

Peripheral but Retained (KEEP_AS_NON_CORE):
- Stress responses (ER, oxidative, heat)
- Cell wall and sphingolipid biosynthesis
- Meiotic cell cycle
- Mitochondrial retrograde signaling

To Remove/Consolidate (MARK_AS_OVER_ANNOTATED):
- 15 generic GO:0005515 (protein binding) annotations - redundant with GO:0031931 and GO:0044877

Recommendations for GO Annotation Improvement

Consolidate protein binding: Replace 15 GO:0005515 annotations with existing complex membership (GO:0031931) and complex binding (GO:0044877) terms.
Add missing annotations: Consider additions for:
TORC1-specific substrate binding (Tap42, Sch9, Ypk3, Stm1)
Amino acid sensing specificity (glutamine, leucine, cysteine)
Rapamycin resistance mechanism
Standardize evidence: Multiple evidence codes for same term (e.g., GO:0004674 has IBA + IEA + IDA) is appropriate and reflects multi-method confirmation.
Improve specificity: Where possible, use specific transactivation terms rather than generic "regulation of" terms.

References for Major Claims

TORC1 Complex Discovery: PMID:12408816
Autophagy Control: PMID:9461583
Nutrient Sensing - Nitrogen: PMID:9461583
Translation Initiation: PMID:8741837
Ribosome Biogenesis: PMID:10198052
Tap42 Phosphorylation: PMID:10329624
Nuclear Localization/rDNA: PMID:16900101
Meiotic Function: PMID:9096347
S6 Phosphorylation: PMID:26582391
Stm1/Ribosome Preservation: PMID:36691768
Glutamine Sensing: PMID:38127619, PMID:34535752