- Fold / Class
- Soluble cytoplasmic non-enzyme (p=1.00); an Abi-family adaptor — structural / signalling, not catalytic.
- Architecture
- ~46% disordered. An N-terminal coiled-coil (33–61), a large disordered mid-region (161–302) and a C-terminal SH3 domain (308–366) — so construct design is the first problem.
- Interaction Pocket
- High-confidence hypothesis (0.86). A residue-level pocket on the SH3 domain (317–361) — the peptide-binding groove an adaptor uses to choose partners.
- Modifications
- Phosphorylation-rich, including sites in the disordered region (S213, S216) and the SH3 (S342).
- Clean Signal
- Soluble; no membrane or amyloid signal.
Model-reported confidence for the headline calls (amber = the load-bearing prediction the rest of the profile builds on). These are model-estimated probabilities that rank and gate each call — not calibrated rates of experimental success.
The Gap
Why This Target Is Still Dark
ABI3 is one of the strongest genetic leads in Alzheimer's disease and one of the weakest mechanistic ones. A rare coding variant (rs616338, p.Ser209Phe) is a genome-wide-significant risk factor for late-onset AD, reported alongside PLCG2 and TREM2 as the evidence that microglia drive AD risk. ABI3 is expressed in microglia in AD and Nasu-Hakola brain. Yet its mechanism remains unresolved — mouse models of Abi3 loss give opposing amyloid phenotypes — and it has no experimental structure in the PDB. It is studied biologically but undrugged (IDG Tbio).
That combination — high genetic priority, near-zero structural information — is exactly where prediction earns its keep: everything below is computed from the canonical 366-residue sequence and derived structural predictions, with no experimental ABI3 structure used as input.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| Coiled-coil | 33–61 | Short N-terminal coiled-coil. |
| Disordered mid-region | 161–302 | ~46% of the chain is disordered; carries the AD risk variant S209F and phospho-sites S213/S216. |
| SH3 domain | 308–366 | The single ordered, foldable module; carries the predicted interaction pocket (317–361) and phospho-site S342. |
The Predicted Pocket
The Predicted Interaction Pocket
Astra places a high-confidence pocket (0.86) on the SH3 domain (residues 317–361) — the surface through which ABI3 would engage the actin-regulatory machinery its family is associated with. Because the pocket sits on the one ordered, foldable module, it is also the part of ABI3 most tractable to express and assay. No known small-molecule binder.
Site: C-terminal SH3 domain (308–366)
Post-Translational & Structural Features
Specific, Testable Residues
- Phosphorylation in the disordered region. Sites such as S213 and S216 sit in the disordered mid-region — a classic regulatory pattern for adaptor proteins (phospho-switching of partner binding).
- Phosphorylation on the SH3 module (S342). A candidate control point for the interaction surface itself.
- No membrane or amyloid signal. A soluble adaptor; the disorder is regulatory, not aggregation-prone.
Recommended Experimental Follow-Up
An Orphan Sequence, Turned Into a Ranked Plan
Each prediction is paired with the experiment that would test it and the readout to watch for.
| Prediction | Experiment | Readout |
|---|---|---|
| SH3 = the foldable module (308–366) | Express the SH3 domain vs full-length | A well-behaved, assay-ready construct |
| SH3 interaction pocket (317–361) | Alanine scan + partner pulldown (AP-MS) | Loss of specific partner binding |
| ~46% disorder map | Limited proteolysis / truncation series | Confirmed domain boundaries |
| S209F in the disordered region | S209F vs WT binding / phospho-state | A structural hypothesis for the variant |
| Phospho-switch (S213/S216/S342) | Phosphomimetic / phospho-null mutants | Change in partner selection |
Scope & Limitations
What This Is — and Isn't
- Prediction, not experiment. These are computational hypotheses to prioritise experiments — not a substitute for a structure or an assay. No result here has been validated in the wet lab.
- The pocket is predicted; no binder or partner is proven. The SH3 surface is a residue-level interaction hypothesis. ABI3's specific incorporation into the WAVE regulatory complex is inferred from Abi-family homology, not from an ABI3-specific reconstitution.
- Biology caveats. ABI3's mechanism in AD microglia is unresolved (knockout models give opposing amyloid phenotypes); treat the disease mechanism as an open question.
All predictions were generated with Orbion's Astra suite from the canonical ABI3 sequence (UniProt Q9P2A4), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q9P2A4 (ABI3, human). uniprot.org.
- [2]Pharos / Illuminating the Druggable Genome. ABI3 target record — Tbio. pharos.nih.gov.
- [3]Sims R., van der Lee S.J., Naj A.C., et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat. Genet. 49(9), 1373–1384 (2017). https://doi.org/10.1038/ng.3916
- [4]Satoh J.-I., Kino Y., Yanaizu M., et al. Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease. Intractable Rare Dis. Res. 6(4), 262–268 (2017). https://doi.org/10.5582/irdr.2017.01073
- [5]Ibanez K.R., Jansen-West K., et al. Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer's disease in a mouse model of Aβ amyloidosis. Sci. Adv. 8(8), eabe3954 (2022). https://doi.org/10.1126/sciadv.abe3954