HdeA qualifier-aware annotation re-review — 2026-08-29

Coverage and provenance

Holdase and ontology decision

HdeA is an ATP-independent, acid-activated in-situ holdase. At neutral pH it is an inactive folded dimer; below pH 3 it becomes a disordered client-binding monomer. [PMID:15911614 “it possesses an ordered conformation that is unable to bind denatured substrate proteins under normal physiological conditions (i.e. at neutral pH) and transforms into a globally disordered conformation that is able to bind substrate proteins under stress conditions (i.e. at a pH below 3)”]

No cached study demonstrates escort to a defined acceptor molecule or destination. HdeA binds clients within the periplasm, prevents aggregation, then releases them when pH is neutralized. Therefore carrier-specific GO:0140309 does not fit. The physical GO:0051082 IDA row is retained as an interim annotation but MODIFY now points machine-readably to NTR holdase chaperone activity, following the CRYAA/project convention. [file:projects/UNFOLDED_PROTEIN_BINDING.md]

GO:0050821 protein stabilization is added as a NEW BP because aggregation suppression is direct: “Functional studies demonstrate that HDEA is activated by a dimer-to-monomer transition at acidic pH, leading to suppression of aggregation by acid-denatured proteins.” PMID:10623550

Refolding decision

GO:0042026 protein refolding is retained as the replacement for the broad physical GO:0006457 protein folding row. The BP does not imply that HdeA catalyzes folding chemistry. PMID:20080625 directly states that HdeA “is capable of independently facilitating the refolding of acid-denatured proteins” and explains that slow release keeps aggregation-sensitive intermediates below their aggregation threshold. This supports involvement in refolding through an environmentally regulated binding-release cycle.

The three experimental GO:0044183 protein folding chaperone rows are retained. Although HdeA is mechanistically a holdase, the direct evidence shows that its binding-release cycle assists the folding process. The core-function prose now separates this refolding assistance from the primary in-situ aggregation-prevention activity.

Other annotation decisions

PR #2740 follow-up — 2026-08-29

PR #2741 follow-up — 2026-08-29