Unfolded Protein Binding Annotation Review

Editor Brief (as of 2026-02-14, revised after full cross-species audit):
GO:0051082 "unfolded protein binding" and GO:0031249 "denatured protein binding" are proposed
for obsoletion (go-ontology#30962).
We reviewed all 148 unique genes (33 human + 115 non-human across 17 species) carrying
experimental annotations to these terms — 5,529 total annotations, 0 PENDING. Each gene's
GO:0051082/GO:0031249 annotation was reclassified to a mechanism-specific MF term.
The 33 human genes provide the primary evidence base with full literature review (see
Human Gene Checklist); the 115 non-human genes validate that the
same decision rules apply consistently across all species (see
Cross-Species Completeness Audit).
Critical finding: GO:0140309 "unfolded protein carrier activity"
was created specifically for TIM carrier-holdases (go-ontology#30552)
and does not fit in-situ holdases (crystallins, sHSPs, CLU). A general "holdase chaperone
activity" term was discussed in #30552 but never created — this is now the primary NTR needed.
Decisions from GO editors are needed on: (1) NTR for general holdase chaperone activity
(non-carrier), (2) whether "misfolded protein sensor activity" should be created for E3
ligases/F-box proteins, (3) how to annotate J-domain co-chaperone MF given that GO:0003767
"co-chaperone activity" is obsolete, and (4) whether GO:0051082 obsoletion should be blocked
until the holdase NTR exists. Detailed review YAMLs are in genes/<SPECIES>/<GENE>/.
Validate with: just validate-all (writes reports/validation-all.tsv).

Slides

Slides (AI generated)

Terminology

These mechanism classes are used throughout this document:

Term	GO term	Definition	ATP?	Example
Foldase	GO:0044183 protein folding chaperone	Actively assists protein folding through iterative binding/release cycles	Yes	GroEL/ES, TRiC/CCT
Holdase	(NTR needed: holdase chaperone activity)	Binds unfolded/misfolded proteins to prevent aggregation in situ; does not actively refold or transport between compartments	No	CRYAB (alpha-crystallin), CLU
Carrier-holdase	GO:0140309 unfolded protein carrier activity	Binds unfolded protein and escorts it between cellular components, preventing aggregation in transit	No	Tim9-Tim10, Tim8-Tim13 (small TIMs)
Foldase/holdase	GO:0044183 + holdase NTR	Context-dependent: can function as foldase or holdase depending on conditions, clients, de novo vs quality control	Yes	HSPA1A (HSP70)
Co-chaperone	(see co-chaperone note)	Binds to chaperone to activate its ATPase and/or deliver substrates; does not independently fold proteins	N/A	DNAJB1 (J-domain), AHSA1 (HSP90 activator)
Disaggregase	GO:0140545	Solubilizes existing protein aggregates	Yes	HSPA1A (with DNAJ + HSPH1)
Sensor	(proposed: misfolded protein sensor activity)	Recognizes misfolded proteins as substrates for degradation (E3 ligase, lectin)	N/A	SYVN1 (HRD1), UGGT1

Decision Rules

How GO:0051082 annotations were reclassified:

Mechanism	Action	Replacement term	Rationale	Example
Foldase (strictly: GroEL/ES, TRiC)	MODIFY	GO:0044183 protein folding chaperone	Active ATP-dependent folding; strictly foldase proteins	PFDN1 (delivers to TRiC)
Foldase/holdase (HSP70 family)	MODIFY	GO:0044183 protein folding chaperone	HSP70 functions as foldase or holdase depending on context (conditions, clients, de novo vs quality control); curators should review per experimental evidence. Holdase aspect awaits holdase NTR	HSPA1A, HSPA8
Co-chaperone, J-domain	MODIFY	GO:0044183 (interim, see co-chaperone note)	J-domain proteins are substrate adaptors and HSP70 ATPase activators, not independent foldases; GO:0044183 used as interim since GO:0003767 "co-chaperone activity" is obsolete	DNAJB1, DNAJA2
Co-chaperone, J-domain holdase	MODIFY	holdase NTR (retain GO:0051082 until NTR created)	J-domain proteins with independent holdase activity (aggregation suppression, no refolding). GO:0140309 is carrier-specific and does not fit; see holdase annotation gap	DNAJB6, DNAJB8
Holdase (sHSP, crystallin, CLU)	MODIFY	holdase NTR (retain GO:0051082 until NTR created)	ATP-independent in-situ aggregation prevention. GO:0140309 does not fit — it was created for carrier-holdases (TIM chaperones); see holdase annotation gap	CRYAA, HSPB6, CLU
Disaggregase (HSP70 subset)	MODIFY	GO:0140545 ATP-dependent protein disaggregase activity	Distinct disaggregation activity	HSPA1A, HSPA1B, HSPA8
Co-chaperone NEF (GrpE-like)	REMOVE	(none — not direct UPB)	Regulates HSP70 nucleotide cycle, does not bind unfolded substrate directly	GRPEL1
ER/quality control sensor	REMOVE or MARK_AS_OVER_ANNOTATED	(none — not chaperones)	Substrate recognition for ligase/GT, not chaperoning	SYVN1, ERLEC1, UGGT1
HSP90 co-chaperone	MARK_AS_OVER_ANNOTATED	(none — co-chaperone, not UPB)	These assist HSP90, not direct unfolded protein binding. AHSA1 is an HSP90 ATPase activator; PTGES3 mechanism less clear (activator? substrate adaptor?)	AHSA1, PTGES3, TMEM67
Other specific MF	MODIFY	Gene-specific term	Function better captured by existing GO term	NPM1 → GO:0140713, AIP → GO:0051879

Impact Summary

Primary GO:0051082 reclassification decisions (mutually exclusive; 33 unique human genes).
Cross-species audit (115 non-human genes) confirms the same mechanism classes apply
universally — see Cross-Species Completeness Audit.

Primary action	Count	Notes
MODIFY → GO:0044183 (foldase)	16	HSP70 family (6), J-domain co-chaperones as interim (4), prefoldin (6, incl. VBP1) — note: HSP70 holdase aspect awaits holdase NTR
MODIFY → holdase NTR (pending)	7	sHSPs/crystallins (3), CLU, SCG5, DNAJB6, DNAJB8 — retain GO:0051082 until NTR created. Also HSPH1 (non-human, not in 33 count). See holdase annotation gap
MODIFY → other specific MF	2	NPM1 (GO:0140713), AIP (GO:0051879)
MARK_AS_OVER_ANNOTATED	5	Sensor/co-chaperone cases where UPB overstates direct activity
REMOVE	3	SYVN1, ERLEC1, GRPEL1
Total	33

Additional non-exclusive co-annotations:

Additional term	Count	Genes
GO:0140545 ATP-dependent protein disaggregase activity	3	HSPA1A, HSPA1B, HSPA8

Note on counts: Some genes may need dual foldase+holdase annotation (e.g. HSP70 family)
depending on experimental context. J-domain co-chaperone counts use GO:0044183 as interim
pending editor guidance on co-chaperone MF representation. 7 holdase genes cannot be properly
reannotated until a general holdase NTR is created — GO:0051082 obsoletion should be blocked
on this.

Before/After Examples

Gene	Old annotation	New annotation	Evidence	Rationale
HSPA1A	GO:0051082 unfolded protein binding (IDA, PMID:21231916)	GO:0044183 protein folding chaperone (foldase) + GO:0140545 disaggregase	IDA	HSP70 is an ATP-dependent foldase; also disaggregates with DNAJ/HSPH1. Holdase aspect awaits holdase NTR
CRYAB	GO:0051082 unfolded protein binding (IDA, PMID:20159986)	holdase NTR (retain GO:0051082 until created)	IDA	sHSP holdase; prevents aggregation in situ without active refolding or inter-compartment transport. GO:0140309 does not fit (carrier-specific)
DNAJB1	GO:0051082 unfolded protein binding (IDA, PMID:21231916)	GO:0044183 protein folding chaperone (interim)	IDA	J-domain co-chaperone: substrate adaptor + HSP70 ATPase activator. Not an independent foldase. GO:0044183 used as interim; see co-chaperone note
SYVN1	GO:0051082 unfolded protein binding (IDA, PMID:14593114)	REMOVE	IDA	HRD1 is an E3 ubiquitin ligase; recognizes misfolded substrates for degradation, not chaperoning. Candidate for proposed "misfolded protein sensor activity"
UGGT1	GO:0051082 unfolded protein binding (IDA, PMID:24790089)	MARK_AS_OVER_ANNOTATED	IDA	Glycoprotein quality sensor for GT activity, not a chaperone
NPM1	GO:0051082 unfolded protein binding (IDA, PMID:20625543)	GO:0140713 histone chaperone activity	IDA	Pentameric histone chaperone; UPB is secondary to core histone chaperoning

Open Ontology Gaps

Ontology changes needed to properly annotate genes in this set:

NTR: general holdase chaperone activity — The most critical gap. GO:0140309
"unfolded protein carrier activity" was created in Nov 2025 specifically for TIM carrier-holdases
(Tim9-Tim10, Tim8-Tim13) that escort unfolded proteins across the mitochondrial IMS
(go-ontology#30552). Its definition
requires escort "between two different cellular components" and it is a child of GO:0140597
"protein carrier chaperone." Val and Pascale acknowledged in #30552 that a more general holdase
term was needed but deferred it: "we thought it would be better to add this specific term as
it was needed immediately for annotation, and add the more general parent 'holdase' when it was
requested for annotation" (Val, 2025-11-04). Raymond also flagged that an ER holdase
(PMID:30287478) doesn't fit GO:0140309. "holdase" is explicitly a BROAD synonym on
GO:0140309, confirming it is not the general holdase term.
We are now requesting this term. 7 genes in this review (CRYAA, CRYAB, HSPB6, CLU, SCG5,
DNAJB6, DNAJB8) plus HSPH1 (non-human) are in-situ holdases that prevent aggregation without
inter-compartment escort. They cannot be annotated to GO:0140309.
Proposed term: "holdase chaperone activity" — Def: "Binding to an unfolded or misfolded
protein to prevent its aggregation without actively catalyzing refolding. The holdase maintains
the client protein in a soluble, folding-competent state." Parent: direct child of
GO:0003674 molecular_function (per #30552 discussion; "protein carrier chaperone" is wrong
for non-carriers). GO:0140309 would become a child of this new term (carrier-holdases are
a subtype of holdases).
Relationship to Raymond's proposal: Raymond (in go-annotation#5581)
proposed creating foldase/holdase subtypes under GO:0051082. We recommend against this because
(a) GO:0051082 is a "binding" term and Val/Pascale want "activity" terms, (b) GO:0044183
already covers foldase, and (c) a standalone holdase term is more composable than a subtype
of a binding term being obsoleted.
Until this NTR is created, GO:0051082 obsoletion should be blocked for holdase genes.
Affects: CRYAA, CRYAB, HSPB6, CLU, SCG5, DNAJB6, DNAJB8, HSPH1.
Misfolded protein sensor activity — Recognition of misfolded protein conformation to
target substrates for quality-control degradation (distinct from chaperone activity). Would
apply to SYVN1, and to non-human genes SAN1 (yeast), Fbxo2 (mouse). Useful for ubiquitin
degradation pathways. Currently these are REMOVE/OVER_ANNOTATED since no appropriate MF
term exists.
Co-chaperone MF representation — GO:0003767 "co-chaperone activity" was deliberately
obsoleted because it "represents a class of gene products rather than a molecular function."
Similarly, GO:0030189 "chaperone activator activity" and all HSP-specific regulator terms
are obsolete. There is currently no MF term that captures what J-domain co-chaperones do
(activate HSP70 ATPase + deliver substrates). GO:0044183 is used as pragmatic interim.
Affects: DNAJB1, DNAJB2, DNAJA2, DNAJA4 and all J-domain proteins across species.

What We Need from GO Editors

[ ] Holdase NTR (BLOCKING): Create general "holdase chaperone activity" term for in-situ holdases. GO:0140309 is carrier-specific (created for TIM chaperones in #30552) and does not fit 7 genes in this review. See holdase annotation gap for proposed def and parentage
[ ] Block GO:0051082 obsoletion until holdase NTR exists — 7 holdase genes have no valid replacement term without it
[ ] Preferred labels: Add "foldase" as exact synonym for GO:0044183; "holdase" should be exact synonym on the new general holdase term (currently BROAD on GO:0140309, which is correct since GO:0140309 is carrier-specific)
[ ] Co-chaperone MF gap: How should J-domain co-chaperone function be annotated? GO:0003767 is obsolete; GO:0044183 is used as interim but obscures the co-chaperone mechanism. Affects all J-domain proteins
[ ] HSP70 dual annotation: Confirm that HSP70-family genes may need both GO:0044183 (foldase) and the holdase NTR depending on experimental context
[ ] PTGES3 co-chaperone mechanism: Clarify whether PTGES3 is an HSP90 activator, substrate adaptor, or both
[ ] Misfolded protein sensor: Decide whether "misfolded protein sensor activity" warrants a new term — affects SYVN1, SAN1, Fbxo2 and ubiquitin degradation pathways
[ ] Proceed with obsoletion of GO:0051082 and GO:0031249 once holdase NTR and other replacement terms are in place

Scope Note: Phase-2 Sensor Batch

This document's primary scope (phase 1) is manual reclassification of existing
GO:0051082 / GO:0031249 annotations. A separate phase 2 batch is reserved for
misfolded-protein sensing and degradation-triage genes that are mechanistically
related but not necessarily in the unfolded/denatured binding annotation set.

Phase 2 candidate genes from deep-research synthesis:

STUB1 (CHIP), UBR1, UBR2, HUWE1 (core misfolded-protein sensor/E3 axis)
BAG3, BAG6 (co-chaperone/triage adapters; secondary sensor-adjacent set)

Phase 2 is a follow-up ontology/annotation effort and should not block phase 1
GO:0051082/GO:0031249 replacement and obsoletion work.

Replacement Terms (detailed)

Existing GO terms used as replacements:

GO:0044183 protein folding chaperone (="foldase") — assists protein folding (existing)
GO:0140545 ATP-dependent protein disaggregase activity — solubilizes protein aggregates (existing)
GO:0140713 histone chaperone activity — for NPM1 (existing)
GO:0051879 Hsp90 protein binding — for AIP (existing; note: binding term, not function)
GO:0000774 adenyl-nucleotide exchange factor activity — core MF for GRPEL1 (UPB removed) (existing)

Not used (despite initial consideration):

GO:0140309 unfolded protein carrier activity — This is a carrier-holdase term created
specifically for TIM chaperones (go-ontology#30552).
Its definition requires escort between cellular components. None of the holdase genes in
this review (crystallins, sHSPs, CLU, SCG5, DNAJB6, DNAJB8) are carrier-holdases.

This project focuses on MF replacement for GO:0051082/GO:0031249. BP terms discussed in
individual gene reviews (for example GO:0030150 in GRPEL1) are not listed as MF replacements here.

Proposed new terms (not yet in GO):

"holdase chaperone activity" — Def: "Binding to an unfolded or misfolded protein to prevent
its aggregation without actively catalyzing refolding. The holdase maintains the client protein
in a soluble, folding-competent state." Parent: direct child of GO:0003674. GO:0140309 (carrier-holdase)
would become a child of this term. This is the primary NTR needed to unblock GO:0051082 obsoletion.
Affects 7 human genes + HSPH1.
"misfolded protein sensor activity" — Def: Recognition of misfolded protein conformation to initiate
quality-control degradation. Distinct from chaperone activity. Useful for ubiquitin degradation pathways.

Proposed refinements to existing terms:

GO:0044183 — Add "foldase" as exact synonym.

Holdase annotation gap

Several genes in this review are holdases rather than foldases. Holdases bind unfolded or
misfolded proteins to prevent their aggregation, but they lack ATPase activity and do not
actively refold substrates. This is mechanistically distinct from the ATP-dependent foldase
activity of HSP70-type chaperones. Some proteins (notably HSP70) can function as both foldase
and holdase depending on conditions, clients, and whether the context is de novo folding or
quality control.

GO:0140309 "unfolded protein carrier activity" does not fit these genes. Review of the
original term request (go-ontology#30552)
shows that GO:0140309 was created in Nov 2025 specifically for TIM carrier-holdases (Tim9-Tim10,
Tim8-Tim13) that escort unfolded proteins across the mitochondrial IMS. Key evidence:

Its definition requires escort "between two different cellular components"
It is a child of GO:0140597 "protein carrier chaperone"
"holdase" is explicitly a BROAD synonym (not exact), because not all holdases are carriers
Val (2025-11-04): "we were aware that there were holdases that did not bind to unfolded
proteins [in transit], but we needed a use case" for the carrier-holdase
Raymond flagged that an ER holdase (PMID:30287478) doesn't fit GO:0140309; Val agreed a
separate holdase term is needed

The holdase genes in this review (CRYAA, CRYAB, HSPB6, CLU, SCG5, DNAJB6, DNAJB8) all prevent
aggregation in situ — they do not escort substrates between compartments. HSPH1 (non-human)
is likewise an in-situ holdase. These genes require a new general "holdase chaperone activity"
term (see Open Ontology Gaps item 1).

Until the holdase NTR is created, these 7 genes should retain GO:0051082 — the obsoletion
of GO:0051082 should be blocked on this NTR.

Co-chaperone note

J-domain (DnaJ/HSP40) proteins are co-chaperones, not independent foldases. They:
- Activate HSP70's ATPase via their J-domain
- Act as substrate adaptors, delivering unfolded clients to HSP70
- Do not independently fold proteins

GO previously had GO:0003767 "co-chaperone activity" but it was deliberately obsoleted because
it "represents a class of gene products rather than a molecular function." Similarly,
GO:0030189 "chaperone activator activity" and all HSP-specific regulator terms are obsolete.

There is currently no active GO MF term for co-chaperone function. GO:0044183 "protein
folding chaperone" is used as a pragmatic interim because J-domain proteins do participate in
the folding process (as part of the HSP70 machine), but this obscures the co-chaperone
mechanism. Editor guidance is requested on how to represent this function.

Note: Some J-domain proteins (DNAJB6, DNAJB8) have independent holdase activity in addition
to their co-chaperone function — these are annotated to GO:0140309 for their holdase activity.

Human Gene Checklist

33 unique human genes are in scope below. HSPA1A appears again in the GO:0031249 subsection
because it has that second term as well; this is not an additional human gene.

Tier 1a - HSP70 family (foldase/holdase, context-dependent)

[x] HSPA1A (P0DMV8) - HSP70, foldase/holdase → MODIFY to GO:0044183 + GO:0140545; holdase aspect awaits holdase NTR
[x] HSPA1B (P0DMV9) - HSP70, foldase/holdase → MODIFY to GO:0044183 + GO:0140545; holdase aspect awaits holdase NTR
[x] HSPA2 (P54652) - HSP70, foldase/holdase → MODIFY to GO:0044183; holdase aspect awaits holdase NTR
[x] HSPA6 (P17066) - HSP70, foldase/holdase → MODIFY to GO:0044183; holdase aspect awaits holdase NTR
[x] HSPA8 (P11142) - HSC70, foldase/holdase → MODIFY to GO:0044183 + GO:0140545; holdase aspect awaits holdase NTR
[x] HSPA1L (P34931) - HSP70, foldase/holdase → MODIFY to GO:0044183; holdase aspect awaits holdase NTR

Tier 1b - J-domain co-chaperones (see co-chaperone note)

[x] DNAJB1 (P25685) - HSP40, foldase-type co-chaperone → MODIFY to GO:0044183 (interim; substrate adaptor + HSP70 ATPase activator)
[x] DNAJB2 (P25686) - HSP40, co-chaperone → MODIFY to GO:0044183 (interim)
[x] DNAJA2 (O60884) - HSP40, foldase-type co-chaperone → MODIFY to GO:0044183 (interim)
[x] DNAJA4 (Q8WW22) - HSP40, co-chaperone → MODIFY to GO:0044183 (interim)
[x] DNAJB6 (O75190) - HSP40, holdase-type co-chaperone → holdase NTR (retain GO:0051082 until created; independent in-situ holdase, not carrier)
[x] DNAJB8 (Q8NHS0) - HSP40, holdase-type co-chaperone → holdase NTR (retain GO:0051082 until created; independent in-situ holdase, not carrier)

Tier 2 - Small HSPs / Holdases

[x] CRYAA (P02489) - alpha-crystallin, holdase → holdase NTR (retain GO:0051082; in-situ holdase, not carrier)
[x] CRYAB (P02511) - alpha-crystallin, holdase → holdase NTR (retain GO:0051082; in-situ holdase, not carrier)
[x] HSPB6 (O14558) - small HSP, holdase → holdase NTR (retain GO:0051082; in-situ holdase, not carrier)

Tier 3 - Prefoldin Complex

[x] PFDN1 (O60925) - prefoldin subunit → MODIFY to GO:0044183
[x] PFDN2 (Q9UHV9) - prefoldin subunit → MODIFY to GO:0044183
[x] PFDN4 (Q9NQP4) - prefoldin subunit → MODIFY to GO:0044183
[x] PFDN5 (Q99471) - prefoldin subunit → MODIFY to GO:0044183 + GO:0003714 (transcription corepressor)
[x] PFDN6 (O15212) - prefoldin subunit → MODIFY to GO:0044183
[x] VBP1 (P61758) - prefoldin subunit 3 → MODIFY to GO:0044183

Tier 4 - ER Quality Control (sensors, not chaperones)

[x] UGGT1 (Q9NYU2) - glycoprotein quality sensor → MARK_AS_OVER_ANNOTATED
[x] ERLEC1 (Q96DZ1) - ER lectin, ERAD → REMOVE
[x] SYVN1 (Q86TM6) - E3 ligase, ERAD → REMOVE

Tier 5 - Other / Unusual

[x] NPM1 (P06748) - nucleophosmin → MODIFY to GO:0140713 + GO:0140142 + GO:0044183 + GO:0019901
[x] CLU (P10909) - clusterin, extracellular holdase → holdase NTR (retain GO:0051082; in-situ/extracellular holdase, not carrier)
[x] SCG5 (P05408) - neuroendocrine protein 7B2 → holdase NTR (retain GO:0051082; secretory pathway holdase, not carrier)
[x] TOMM20 (Q15388) - mitochondrial import receptor → MARK_AS_OVER_ANNOTATED
[x] GRPEL1 (Q9HAV7) - GrpE homolog (NEF) → REMOVE (not direct unfolded-substrate binder; core MF GO:0000774)
[x] AIP (O00170) - AH receptor interacting protein → MODIFY to GO:0051879
[x] AHSA1 (O95433) - HSP90 ATPase activator co-chaperone → MARK_AS_OVER_ANNOTATED
[x] PTGES3 (Q15185) - HSP90 co-chaperone (mechanism unclear: activator? substrate adaptor?) / PGE synthase → MARK_AS_OVER_ANNOTATED
[x] TMEM67 (Q5HYA8) - meckelin → MARK_AS_OVER_ANNOTATED

GO:0031249 (denatured protein binding)

HSPA1A (P0DMV8) - already in Tier 1 (same gene; listed here because it also has GO:0031249)
[x] SAN1 (yeast) - E3 ligase, misfolded protein sensor → MODIFY GO:0031249 to GO:0051787 (misfolded protein binding)
[x] Fbxo2 (mouse) - F-box protein, glycoprotein sensor → MODIFY GO:0031249 (glycan-mediated recognition, not general denatured protein binding)
[x] HSPH1 (hamster) - Hsp110, holdase → MODIFY GO:0031249 to holdase NTR (retain GO:0031249 until created) + core NEF function (GO:0000774)

Categories of Annotated Proteins (all species)

All 148 genes organized by mechanism class (human + non-human combined):

#	Category	Genes	Decision pattern
1	HSP70 foldase/holdase	HSPA1A/B, HSPA2, HSPA6, HSPA8, HSPA1L (human); SSA1-4, SSB1-2, SSQ1, SSZ1, KAR2, LHS1 (yeast); DnaK (E. coli); Hspa8 (mouse, rat); Hspa5/BiP (rat)	MODIFY → GO:0044183; holdase NTR pending
2	HSP90 system	AHSA1, PTGES3, AIP (human); HSP82, HSC82, CPR6, CPR7, CDC37 (yeast); CDC37 (C. albicans); Hsp83 (fly)	MODIFY or OVER_ANNOTATED
3	J-domain co-chaperones	DNAJB1, DNAJB2, DNAJA2, DNAJA4 (human); DNAJB6, DNAJB8 (human, holdase-type); YDJ1, MDJ1, APJ1 (yeast); JEM1 (yeast, C. albicans); DnaJ (E. coli); Dnaja3, Dnajb11 (mouse)	MODIFY → GO:0044183 (interim); holdase-type → holdase NTR
4	sHSPs/holdases	CRYAA, CRYAB, HSPB6 (human); CLU, SCG5 (human); CRYAA (bovine); cryaa/cryaba/cryabb (zebrafish); HSP26 (yeast); Hsp22/23/26/27 (fly); HSP17.7 (Arabidopsis); HSPH1 (hamster)	MODIFY → holdase NTR; retain GO:0051082 until NTR created
5	Chaperonin/TRiC/CCT	TCP1, CCT2-8 (yeast); GroEL (E. coli); HSP60, HSP10 (yeast)	MODIFY → GO:0044183
6	Prefoldin	PFDN1-6, VBP1 (human); PFD1, EGD1, EGD2 (yeast)	MODIFY → GO:0044183
7	Disaggregase	HSP104 (yeast)	MODIFY → GO:0044183 (also GO:0140545)
8	ER quality control	UGGT1, ERLEC1, SYVN1 (human); Uggt1 (rat); CNE1, EPS1, PDI1, EUG1, ROT1, IRE1 (yeast); IRE1 (T. reesei); CSH3 (C. albicans); Edem2 (fly)	OVER_ANNOTATED or REMOVE (sensors, not chaperones)
9	Mito import/assembly	TOMM20, GRPEL1 (human); TIM9, TIM10, COX20, PET100, SHY1, ATP10, ATP11 (yeast); Grpel2 (mouse); cia30 (N. crassa)	OVER_ANNOTATED (assembly factors) or MODIFY (TIMs → GO:0140309)
10	Ubiquitin/QC sensor	SYVN1 (human); SAN1 (yeast); Fbxo2 (mouse); slrP (Salmonella)	REMOVE or MODIFY to GO:0051787
11	Periplasmic chaperones	SurA, Skp, Spy, SecB, HdeA, HdeB, SlyD, CpxP (E. coli)	MODIFY → GO:0044183 (holdase/chaperone)
12	Ribosome assembly	SQT1, SYO1, YAR1, RRB1, TSR4, PNO1, ACL4, SHQ1, BTT1 (yeast)	MODIFY → GO:0044183 or OVER_ANNOTATED
13	Peroxiredoxin/redox chaperones	TSA1 (yeast); pmp20, tpx1 (S. pombe); CnoX, RidA (E. coli)	MODIFY → GO:0044183 (stress-activated holdase)
14	Membrane protein chaperones	SHR3, PHO86, GSF2, CHS7, NSG1, NSG2, VMA22, VPS45 (yeast)	MODIFY or OVER_ANNOTATED
15	Other	NPM1, TMEM67 (human); NAP1, GET3 (yeast); St13, Serpinh1 (mouse/rat); Nmnat (fly); nud-1, hsp-12.3, hsp-12.6 (worm); tigA (A. niger); GIP1 (Arabidopsis)	Gene-specific decisions

Cross-Species Completeness Audit

All experimental annotations to GO:0051082 and GO:0031249 across all species have been
reviewed. The Human Gene Checklist provides detailed mechanism-level
analysis with full literature review; this section documents that the same decision rules
apply consistently across species.

Coverage

Metric	Count
Unique gene reviews (by UniProt ID)	148
Human genes (primary analysis)	33
Non-human genes	115
Species covered	17
Total annotations reviewed	5,529
Remaining PENDING	0

GO:0051082/GO:0031249 decisions (non-human genes only)

Decision	Count	Description
MODIFY → GO:0044183 or holdase NTR	88	Genuine chaperones reclassified to mechanism-specific terms
MARK_AS_OVER_ANNOTATED	23	Assembly factors, sensors, co-chaperones where UPB overstates activity
ACCEPT (retain GO:0051082)	3	Genes where GO:0051082 remains best available term
KEEP_AS_NON_CORE	2	UPB is secondary to primary function (ATP11, VMA22)
REMOVE	2	Misannotations (slrP/Salmonella, hsp-12.6/worm)

Species breakdown

Species	Genes	Notes
S. cerevisiae	67	Largest set; covers all 14 mechanism classes
E. coli	13	Major bacterial chaperone repertoire including periplasmic holdases (SurA, Skp, Spy, HdeA/B, SecB) with no human orthologs
D. melanogaster	7	sHSPs (Hsp22-27), Hsp83 (HSP90), Edem2 (ERAD sensor), Nmnat
M. musculus	6	Orthologs of human genes; Hspa8 was largest review (240 annotations)
R. norvegicus	4	Hspa5/BiP (101 annotations), Hspa8, St13, Uggt1
C. albicans	3	CDC37, CSH3, JEM1
D. rerio	3	Crystallin holdases: cryaa, cryaba, cryabb
C. elegans	3	sHSPs (hsp-12.3, hsp-12.6) and nud-1
S. pombe	2	Peroxiredoxins: pmp20, tpx1
A. thaliana	1	HSP17.7 (cytosolic class II sHSP holdase)
B. taurus	1	CRYAA (classic holdase reference)
N. crassa	1	cia30 (complex I assembly factor, not general UPB)
A. niger	1	tigA (PDI family ER chaperone)
S. typhimurium	1	slrP (T3SS effector E3 ligase — misannotation removed)
T. reesei	1	IRE1 (UPR sensor, not chaperone)
Chinese hamster	1	HSPH1 (Hsp110, holdase + NEF)

Notable non-human findings

These cases added genuinely new mechanistic insights beyond what the human gene reviews
established:

SlrP (S. typhimurium) — Misannotation identified and removed. SlrP is a T3SS
effector E3 ubiquitin ligase that binds the ER chaperone ERdj3; the GO:0051082 annotation
was based on co-IP with ERdj3, misinterpreted as unfolded protein binding. SlrP disrupts
ERdj3's chaperone function rather than acting as a chaperone itself.
E. coli periplasmic chaperones (SurA, Skp, Spy, HdeA/B, SecB, CpxP, SlyD) —
Bacterial-specific holdase/chaperone category with no human orthologs. SurA is a holdase
that escorts OMPs to the BAM complex; Spy and HdeA/B are acid-activated holdases; SecB
is a secretion-coupled holdase. All MODIFY → GO:0044183. These validate the foldase/holdase
framework in a phylogenetically distant lineage.
CnoX (E. coli) — Redox-activated holdase with thioredoxin domain. Interesting
mechanistic variant: becomes an active holdase specifically under oxidative stress when
its Cys residues are oxidized. Supports the holdase NTR need.
Assembly factors (ATP10, PET100, COX20, SHY1, cia30) — Single-client assembly
chaperones for respiratory chain complexes. These bind specific subunits during complex
assembly, not unfolded proteins generally. All MARK_AS_OVER_ANNOTATED. GO:0140777
(protein-containing complex stabilizing activity) proposed as replacement for some.
IRE1 (yeast + T. reesei) — UPR sensor kinase/endoribonuclease. Detects unfolded
proteins in the ER lumen as a signaling sensor, not a chaperone. Cross-kingdom confirmation
of OVER_ANNOTATED. The T. reesei review also flagged metazoan-specific GO terms
(IRE1-TRAF2-ASK1 complex) that are biologically impossible in fungi.
Peroxiredoxins (TSA1, pmp20, tpx1) — Dual-function: peroxidase at low oxidative
stress, holdase chaperone at high stress (after overoxidation of catalytic Cys). Confirms
that GO:0051082 is appropriate for the chaperone function but should become holdase NTR.

Full non-human gene table (click to expand)

Gene	Species	UniProt	Annotations	GO:0051082 decision	Notes
HSP17.7	A. thaliana	O81822	14	MODIFY (holdase NTR)	Cytosolic class II sHSP
tigA	A. niger	Q00216	7	MODIFY → GO:0044183	PDI family ER chaperone
CRYAA	B. taurus	P02470	25	MODIFY (holdase NTR)	Classic holdase reference
CDC37	C. albicans	Q8X1E6	23	MODIFY	HSP90 co-chaperone
CSH3	C. albicans	A0A1D8PLU5	17	MODIFY	ER oxidoreductase
JEM1	C. albicans	A0A1D8PIB5	11	MODIFY	ER DnaJ co-chaperone
hsp-12.3	C. elegans	Q20164	6	ACCEPT	sHSP
hsp-12.6	C. elegans	G5EE36	7	REMOVE	UPB not well-supported
nud-1	C. elegans	G5EE74	15	MODIFY	Nudix hydrolase
HSPH1	Chinese hamster	Q60446	12	MODIFY (holdase NTR)	Hsp110 holdase + NEF
cryaa	D. rerio	Q8UUZ6	17	MODIFY (holdase NTR)	Crystallin holdase
cryaba	D. rerio	Q9PUR2	16	MODIFY (holdase NTR)	Crystallin holdase
cryabb	D. rerio	A0A8M9Q8E3	19	MODIFY (holdase NTR)	Crystallin holdase
Hsp22	D. melanogaster	P02515	18	MODIFY (holdase NTR)	sHSP
Hsp23	D. melanogaster	P02516	22	MODIFY (holdase NTR)	sHSP
Hsp26	D. melanogaster	P02517	22	MODIFY (holdase NTR)	sHSP
Hsp27	D. melanogaster	P02518	24	MODIFY (holdase NTR)	sHSP
Hsp83	D. melanogaster	P02828	54	MODIFY → GO:0044183	HSP90 ortholog
Nmnat	D. melanogaster	Q9VC03	32	MODIFY	Neuroprotective chaperone
Edem2	D. melanogaster	Q9VK27	23	OVER_ANNOTATED	ERAD sensor, not chaperone
CnoX	E. coli	P77395	12	MODIFY → GO:0044183	Redox-activated holdase
CpxP	E. coli	P0AE85	11	OVER_ANNOTATED	Cpx pathway adaptor
DnaJ	E. coli	P08622	48	MODIFY → GO:0044183	J-domain co-chaperone
DnaK	E. coli	P0A6Y8	61	MODIFY → GO:0044183	HSP70 foldase/holdase
GroEL	E. coli	P0A6F5	64	MODIFY → GO:0044183	Chaperonin
HdeA	E. coli	P0AES9	14	MODIFY → GO:0044183	Acid-activated holdase
HdeB	E. coli	P0AET2	8	MODIFY → GO:0044183	Acid-activated holdase
RidA	E. coli	P0AF93	22	OVER_ANNOTATED	Reactive intermediate deaminase
SecB	E. coli	P0AG86	27	MODIFY → GO:0044183	Secretion chaperone
Skp	E. coli	P0AEU7	34	MODIFY → GO:0044183	Periplasmic holdase
SlyD	E. coli	P0A9K9	35	MODIFY → GO:0044183	FKBP-type PPIase/chaperone
Spy	E. coli	P77754	11	MODIFY → GO:0044183	Periplasmic holdase
surA	E. coli	P0ABZ6	31	MODIFY → GO:0044183	Periplasmic OMP holdase
Dnaja3	M. musculus	Q99M87	81	MODIFY → GO:0044183	Mitochondrial J-domain co-chaperone
Dnajb11	M. musculus	Q99KV1	33	MODIFY → GO:0044183	ER J-domain co-chaperone
Fbxo2	M. musculus	Q80UW2	44	MODIFY	Glycoprotein QC sensor (GO:0031249)
Grpel2	M. musculus	O88396	15	MODIFY	Mitochondrial NEF
Hspa8	M. musculus	P63017	240	MODIFY → GO:0044183	HSC70 foldase/holdase
Serpinh1	M. musculus	P19324	26	MODIFY → GO:0044183	Collagen chaperone
cia30	N. crassa	O42636	7	OVER_ANNOTATED	Complex I assembly factor
Hspa5	R. norvegicus	P06761	101	MODIFY → GO:0044183	BiP/GRP78 ER HSP70
Hspa8	R. norvegicus	P63018	208	MODIFY → GO:0044183	HSC70 foldase/holdase
St13	R. norvegicus	P50503	23	MODIFY	HSP70/HSP90 co-chaperone
Uggt1	R. norvegicus	Q9JLA3	26	OVER_ANNOTATED	Glycoprotein QC sensor
pmp20	S. pombe	O14313	18	MODIFY → GO:0044183	Peroxiredoxin/holdase
tpx1	S. pombe	O74887	35	MODIFY → GO:0044183	Peroxiredoxin/holdase
IRE1	T. reesei	G0RBE3	21	OVER_ANNOTATED	UPR sensor, not chaperone
slrP	S. typhimurium	Q8ZQQ2	16	REMOVE	T3SS effector E3 ligase (misannotation)
ACL4	S. cerevisiae	Q03771	18	MODIFY	Ribosome assembly
APJ1	S. cerevisiae	P53940	26	MODIFY	J-domain co-chaperone
ATP10	S. cerevisiae	P18496	14	OVER_ANNOTATED	Atp6p assembly factor
ATP11	S. cerevisiae	P32453	16	NON_CORE	Atp12p assembly factor
BTT1	S. cerevisiae	P40314	15	MODIFY	Ribosome assembly
CCT2	S. cerevisiae	P39076	21	MODIFY → GO:0044183	TRiC/CCT subunit
CCT3	S. cerevisiae	P39077	17	MODIFY → GO:0044183	TRiC/CCT subunit
CCT4	S. cerevisiae	P39078	19	MODIFY → GO:0044183	TRiC/CCT subunit
CCT5	S. cerevisiae	P40413	17	MODIFY → GO:0044183	TRiC/CCT subunit
CCT6	S. cerevisiae	P39079	17	MODIFY → GO:0044183	TRiC/CCT subunit
CCT7	S. cerevisiae	P42943	16	MODIFY → GO:0044183	TRiC/CCT subunit
CCT8	S. cerevisiae	P47079	20	MODIFY → GO:0044183	TRiC/CCT subunit
CDC37	S. cerevisiae	P06101	23	OVER_ANNOTATED	HSP90 co-chaperone
CHS7	S. cerevisiae	P38843	20	MODIFY	Chitin synthase chaperone
CNE1	S. cerevisiae	P27825	17	OVER_ANNOTATED	ER lectin
COX20	S. cerevisiae	Q04935	12	OVER_ANNOTATED	Cox2p assembly factor
CPR6	S. cerevisiae	P53691	28	OVER_ANNOTATED	HSP90 co-chaperone
CPR7	S. cerevisiae	P47103	21	OVER_ANNOTATED	HSP90 co-chaperone
EGD1	S. cerevisiae	Q02642	19	MODIFY → GO:0044183	NAC complex
EGD2	S. cerevisiae	P38879	22	MODIFY → GO:0044183	NAC complex
EPS1	S. cerevisiae	P40557	15	OVER_ANNOTATED	ER QC factor
EUG1	S. cerevisiae	P32474	24	OVER_ANNOTATED	PDI homolog
GET3	S. cerevisiae	Q12154	64	MODIFY	TA protein chaperone
GSF2	S. cerevisiae	Q04697	9	MODIFY	Glucose transporter chaperone
HSC82	S. cerevisiae	P15108	47	MODIFY → GO:0044183	HSP90
HSP10	S. cerevisiae	P38910	21	OVER_ANNOTATED	GroES co-chaperonin
HSP104	S. cerevisiae	P31539	46	MODIFY → GO:0044183	Disaggregase
HSP26	S. cerevisiae	P15992	16	MODIFY (holdase NTR)	sHSP holdase
HSP60	S. cerevisiae	P19882	47	MODIFY → GO:0044183	Chaperonin
HSP82	S. cerevisiae	P02829	73	MODIFY → GO:0044183	HSP90
IRE1	S. cerevisiae	P32361	46	OVER_ANNOTATED	UPR sensor
JEM1	S. cerevisiae	P40358	15	MODIFY	ER J-domain co-chaperone
KAR2	S. cerevisiae	P16474	42	MODIFY → GO:0044183	ER HSP70 (BiP)
LHS1	S. cerevisiae	P36016	22	MODIFY → GO:0044183	ER HSP70-like
MDJ1	S. cerevisiae	P35191	25	MODIFY → GO:0044183	Mito J-domain
NAP1	S. cerevisiae	P25293	60	MODIFY	Histone chaperone
NSG1	S. cerevisiae	P38837	16	OVER_ANNOTATED	Sterol-binding
NSG2	S. cerevisiae	P53898	8	OVER_ANNOTATED	Sterol-binding
PDI1	S. cerevisiae	P17967	32	OVER_ANNOTATED	Protein disulfide isomerase
PET100	S. cerevisiae	P38958	12	OVER_ANNOTATED	Cox assembly factor
PFD1	S. cerevisiae	P46988	20	MODIFY → GO:0044183	Prefoldin subunit
PHO86	S. cerevisiae	P46956	12	MODIFY	Phosphate transporter chaperone
PNO1	S. cerevisiae	Q99216	18	OVER_ANNOTATED	Ribosome biogenesis
ROT1	S. cerevisiae	Q03691	23	MODIFY	ER chaperone
RRB1	S. cerevisiae	Q04225	11	MODIFY	Ribosome assembly
SAN1	S. cerevisiae	P22470	20	MODIFY (GO:0051787)	E3 ligase QC sensor (GO:0031249)
SHQ1	S. cerevisiae	P40486	12	MODIFY	H/ACA snoRNP assembly
SHR3	S. cerevisiae	Q02774	18	MODIFY	Amino acid permease chaperone
SHY1	S. cerevisiae	P53266	14	OVER_ANNOTATED	Cox assembly factor
SQT1	S. cerevisiae	P35184	9	MODIFY	Ribosome assembly
SSA1	S. cerevisiae	P10591	71	MODIFY → GO:0044183	HSP70
SSA2	S. cerevisiae	P10592	58	MODIFY → GO:0044183	HSP70
SSA3	S. cerevisiae	P09435	26	MODIFY → GO:0044183	HSP70
SSA4	S. cerevisiae	P22202	25	MODIFY → GO:0044183	HSP70
SSB1/2	S. cerevisiae	P10080/P40150	32/39	MODIFY → GO:0044183	Ribosome-associated HSP70
SSQ1	S. cerevisiae	Q05931	29	MODIFY → GO:0044183	Mito HSP70
SSZ1	S. cerevisiae	P38788	30	MODIFY → GO:0044183	RAC HSP70
SYO1	S. cerevisiae	Q07395	12	MODIFY	Ribosome assembly
TCP1	S. cerevisiae	P12612	23	MODIFY → GO:0044183	TRiC subunit
TIM9	S. cerevisiae	O74700	30	MODIFY → GO:0140309	Carrier-holdase
TIM10	S. cerevisiae	P87108	34	MODIFY → GO:0140309	Carrier-holdase
TSA1	S. cerevisiae	P34760	60	MODIFY → GO:0044183	Peroxiredoxin/holdase
TSR4	S. cerevisiae	P25040	15	MODIFY → GO:0044183	Ribosome assembly chaperone
VMA22	S. cerevisiae	P38784	9	NON_CORE	V-ATPase assembly
VPS45	S. cerevisiae	P38932	35	OVER_ANNOTATED	SNARE regulator
YAR1	S. cerevisiae	P46683	19	MODIFY	Rps3 chaperone
YDJ1	S. cerevisiae	P25491	49	MODIFY → GO:0044183	J-domain co-chaperone

Session Log

Curation session notes (click to expand)

2026-02-20 (session 10 - CARRIER SEMANTICS DISCUSSION)

Core issue raised: The "protein carrier activity" terms (GO:0140597, GO:0140309) have problematic definitions centered on "moving along with the target protein"
Suzi (SGD) responded to Tim44/Tim22 reannotation request: "I don't see evidence that TIM22 carries and moves along with the target protein, it looks to be called a pore/channel, and I read that as being fairly stationary"
This is a correct reading — the "moving along with" language in GO:0140597 is causing real confusion for curators
Two proposals discussed for resolving the chaperone grouping problem:
Option A: Rename "molecular carrier activity" branch to "molecular chaperone" focused on protection — "Protecting the cell or a protein from aggregation, misfolding, degradation, or mistargeting during folding or delivery"
- Problem: this is more of a role than a molecular activity — same issue that led to obsoletion of GO:0003767 "co-chaperone activity"
Option B: No grouping term — mechanism-specific terms only (foldase, holdase, carrier-holdase, disaggregase each as direct children of molecular_function)
- Cleaner ontologically; different chaperones use genuinely different mechanisms
- Loses ability to query "all chaperones" via a single GO MF term, but that's what protein families (InterPro/Pfam) are for
Consensus leaning toward Option B with additional suggestion to revise/obsolete GO:0140597 "protein carrier chaperone" whose definition is the root of the curator confusion
This must be resolved before proceeding with holdase NTR or other ontology changes — the parentage and grouping structure affects everything downstream
Current GO hierarchy causing the problem:
GO:0140104 "molecular carrier activity" → GO:0140597 "protein carrier chaperone" → GO:0140309 "unfolded protein carrier activity"
The "carrier" semantics don't apply to in-situ holdases (sHSPs, crystallins, CLU) OR to many other chaperones

2026-02-14 (session 9 - CROSS-SPECIES COMPLETENESS AUDIT)

Full cross-species audit completed: queried QuickGO for ALL experimental annotations to GO:0051082 and GO:0031249
Found 148 unique genes (by UniProt ID) across 17 species; 33 human were already reviewed
115 non-human genes identified; most yeast genes (67) had been reviewed in previous sessions
Newly reviewed in this session: 13 genes
E. coli: dnaJ, groEL, dnaK, slyD, cpxP, hdeA, hdeB, skp, ridA, secB, cnoX, spy, surA
Yeast: ATP10
Mouse: Dnaja3, Hspa8 (240 annotations — largest review), Dnajb11, Grpel2, Serpinh1
Rat: Hspa5 (101 annotations)
Fly: Edem2
Bovine: CRYAA
N. crassa: cia30
A. niger: tigA
Salmonella: slrP (misannotation — REMOVED)
T. reesei/C. glabrata: IRE1
Arabidopsis: HSP17.7
Drosophila: Hsp26
5,529 total annotations reviewed, 0 PENDING remaining
Decision distribution for non-human genes: 88 MODIFY, 23 OVER_ANNOTATED, 3 ACCEPT, 2 NON_CORE, 2 REMOVE
Same mechanism classes apply universally across species — validates the human-derived decision rules
Notable findings: SlrP misannotation (T3SS effector, not UPB), CnoX redox-activated holdase, peroxiredoxin dual function
Added Cross-Species Completeness Audit section to project doc with full gene table
Updated editor brief to reflect full scope (148 genes, 17 species)

2026-02-11 (session 8 - GO:0140309 CARRIER CORRECTION)

Critical correction: GO:0140309 is NOT a general holdase term
Reviewed full discussion in go-ontology#30552
GO:0140309 was created Nov 2025 specifically for TIM carrier-holdases (Tim9-Tim10, Tim8-Tim13)
Definition requires escort "between two different cellular components"; child of GO:0140597 "protein carrier chaperone"
"holdase" is BROAD synonym (not exact), confirming it's not the general holdase term
Val acknowledged general holdase term needed but deferred: "add the more general parent 'holdase' when it was requested for annotation"
Raymond flagged ER holdase (PMID:30287478) doesn't fit; Val agreed separate term needed
All 7 holdase genes (CRYAA, CRYAB, HSPB6, CLU, SCG5, DNAJB6, DNAJB8) + HSPH1 changed from GO:0140309 to "holdase NTR pending"
Primary NTR is now "holdase chaperone activity" (general, non-carrier) — GO:0140309 would become a child
GO:0051082 obsoletion should be blocked until holdase NTR exists
Added note on Raymond's foldase/holdase subtype proposal and why standalone term is preferred
Fixed small Tims example (they ARE carrier-holdases, so were wrong as example of non-carrier holdases)
HSP70 holdase aspect now references holdase NTR instead of GO:0140309

2026-02-11 (session 7 - EDITOR FEEDBACK)

Major corrections based on GO editor review:
DNAJ proteins reclassified from "foldase" to "co-chaperone" (substrate adaptors + HSP70 ATPase activators)
HSP70 noted as context-dependent foldase/holdase (varies by conditions, clients, de novo vs QC)
Holdase replacement term changed from GO:0044183 placeholder to GO:0140309 "unfolded protein carrier activity"
Proposed refinement of GO:0140309 def to foreground aggregation prevention
Proposed "holdase" as exact (not broad) synonym on GO:0140309
Flagged carrier/escort semantics issue: does GO:0140309 fit in-situ holdases (crystallins)?
AHSA1 confirmed as HSP90 ATPase activator; PTGES3 mechanism unclear (activator? adaptor?)
Note: GO:0003767 "co-chaperone activity" is deliberately obsolete — no MF term exists for J-domain function
"misfolded protein sensor activity" confirmed useful for ubiquitin degradation pathways
Biologist-friendly labels: "foldase" for GO:0044183, "holdase" for GO:0140309
Gene checklist restructured: Tier 1a (HSP70 foldase/holdase), Tier 1b (J-domain co-chaperones)
Gene review YAMLs not yet updated — deferred pending editor decisions on holdase carrier semantics and co-chaperone MF representation

2026-02-09 (session 6 - NON-HUMAN GENES)

3 non-human genes completed: SAN1 (yeast), Fbxo2 (mouse), HSPH1 (Chinese hamster/CRIGR)
SAN1: E3 ubiquitin ligase for nuclear protein quality control; GO:0031249 → MODIFY to GO:0051787 (misfolded protein binding)
Fbxo2: SCF(Fbxo2) substrate adaptor recognizing N-glycans on misfolded glycoproteins; GO:0031249 addressed via glycan-mediated mechanism
HSPH1: Hsp110 holdase + NEF for Hsp70; GO:0031249 → MODIFY to GO:0044183 (holdase placeholder)
All 3 validate (0 errors; minor warnings about deep research cross-referencing)
All 36 genes (33 human + 3 non-human) now complete

2026-02-09 (session 5 - COMPLETION)

All 33 human genes fully complete: 0 PENDING annotations, all core_functions populated
Used parallel annotation-reviewer and core-function-synthesizer agents across 5 context windows
HSPA8 was the largest gene (234 annotations) - completed with dedicated agent
Prefoldin subunits (PFDN2-6, VBP1) batch-reviewed efficiently given shared function
HSPA1A core_functions added last (agent got stuck, completed manually using HSPA1B as template)
SYVN1 had minor supporting_text encoding issues (Greek alpha characters) - fixed
Key insight: many genes annotated to GO:0051082 have distinct mechanisms (foldase vs holdase vs disaggregase vs sensor) that existing GO terms can capture
Holdase-type genes (DNAJB6, DNAJB8, CRYAA, CRYAB, HSPB6, CLU) annotated to GO:0044183 with notes about holdase distinction pending ontology term creation

2026-02-09 (session 2 - status update)

Comprehensive status audit performed
26/33 human genes had at least partial review (GO:0051082 annotation addressed)
Most genes had many remaining PENDING annotations (e.g. HSPA1A: 193 PENDING out of 197 total)
HSPA8 was the largest gene (234 annotations) and still entirely PENDING
Prefoldin subunits (PFDN2-6, VBP1) were mostly stubs - batch-reviewed given shared function

2026-02-09 (session 1)

Project initiated based on go-ontology#30962
~189 experimental annotations across all species to GO:0051082
5 experimental annotations to GO:0031249
Key ontological debate: should we create holdase vs foldase subtypes, or use existing terms?
Raymond suggests: ATP-dependent (foldase) vs ATP-independent (holdase) split
Val notes SAN1 and Fbxo2 are "misfolded protein sensors" rather than chaperones
No "holdase" GO term exists yet - GO:0044183 "protein folding chaperone" exists for foldase
The prefoldin complex (PFDN1-6) functions as a co-chaperone for TRiC/CCT, delivering substrates

Warnings (3)