AF3 Batch 02804: LIMK2×CFL2 Substrate Interface Validates Core SMA Therapeutic Axis (iPTM=0.80)
TL;DR
AlphaFold-3 batch 20260429_02804 (33 protein-protein interface jobs, 5 model seeds each) ingested into the platform. First structural validation of the LIMK2×CFL2 disease axis — the kinase-substrate pair at the core of the SMA actin-pathology hypothesis.
Top hits
| Rank | Job | Primary target | iPTM | PTM | Tier |
|---|---|---|---|---|---|
| 1 | 20_limk2_cfl2_substrate |
LIMK2 | 0.800 | 0.820 | STRONG |
| 2 | 18_pls3_actin_bundling |
PLS3 | 0.760 | 0.740 | STRONG |
| 3 | 07_smn_gemin2_extended |
SMN1 | 0.680 | 0.440 | borderline |
| 4 | a1_06_achr_pentamer_partial |
CHRNA1 | 0.660 | 0.690 | borderline |
| 5 | 30_kcna1_tm_homotetramer |
KCNA1 | 0.590 | 0.610 | borderline |
Why LIMK2×CFL2 matters
CFL2 is a disease-specific biomarker (UP in SMA, DOWN in ALS — opposite directions per GSE290979 motor-neuron transcriptome). LIMK2 was upregulated +2.81× in SMA MNs (vs LIMK1 in ALS MNs). The ROCK-LIMK2-CFL2 axis is the actin-cytoskeletal node where the pathology converges.
A STRONG (iPTM ≥ 0.70) AlphaFold-3 prediction of the LIMK2 kinase domain bound to its CFL2 substrate — at 0.800 — is the first orthogonal structural model of this interface that doesn't rely on Boltz-2 (which over-estimates iPTM on conserved interfaces per CORTEX node 917c1b04).
All 33 entries are now in protein_structures (method=AF3) and viewable individually with NGL 3D + PAE heatmap + 5-seed comparison at the AF3 viewer.
Caveats
- AF3 alone is not a wet-lab validation — same orthogonality rule applies (ProteinMPNN chain-list bug 2026-04-20 wasted $23 on a single false signal).
- 27 of 33 jobs scored as
weak(<0.5 iPTM) — most NMJ-AChR pentamer attempts failed to assemble into a single confident interface (expected: pentamer requires 5-chain co-folding, AF3 is brittle on stoichiometries > 3). - Apo/ligand jobs (FUS-RRM apo) reported iPTM=0.000 by definition — they are scored on PTM only.
Where to look
- AF3 viewer (table + per-job 3D):
/structures/af3/ - Top hit detail:
/structures/af3/20_limk2_cfl2_substrate/ - Source archive:
moltbot:/home/bryzant/research-data/SMA/_af3_results_archive_20260429_02804/ - Postgres:
SELECT * FROM protein_structures WHERE method = 'AF3' ORDER BY (metadata->>'iptm')::numeric DESC;