STRC × TMEM145 interactions — literature status
Source agents: Domain 3 (Sonnet 4.6), cross-checked against Domain 1/2, 2026-04-23. Consumer: hydrogel_phase4e_cochlear_pkpd.py (KD_TMEM145_M), hydrogel_phase4h_endogenous_strc_competition.py (competition math), h03 AAV dosing, h26 avidity design.
What is known
| Evidence class | Source | Finding |
|---|---|---|
| Coimmunoprecipitation | 2026-04-17-derstroff-tmem145-ohc-stereocilia Fig S11 | STRC × TMEM145 interact in native OHC (CoIP positive) |
| Pull-down | Same + NatComms 2025 (Reimann lab) | Confirmed pair |
| nanoSPD localization | Derstroff 2026 | TMEM145 and STRC co-localize at OHC bundle |
| AF3 ipTM | Derstroff 2026 + internal Phase 3 (h09) | 0.71–0.79 (structural plausibility, not affinity) |
| Genetic | Verpy 2008 Nature + DFNB16 clinical | STRC loss → OHC bundle disruption (functional interaction) |
What is NOT known
There is zero published SPR, BLI, ITC, or fluorescence measurement of STRC × TMEM145 binding affinity.
- Derstroff 2026 SI → only Fig S11 (CoIP band quantification). Nothing quantitative.
- NatComms 2025 parallel paper → CoIP and pull-down only.
- Verpy 2011 → no binding data.
- No other paper in literature reports biophysical Kd.
Red flag in current h09 Phase 4 models
| Model constant | Value | Problem |
|---|---|---|
KD_TMEM145_M = 100e-9 (Phase 4e) | 100 nM | Derived from AF3 ipTM 0.68 via heuristic mapping. AF3 ipTM is NOT calibrated to affinity. |
| WT STRC × TMEM145 Kd (Phase 4h assumption) | 10 nM | Completely unsourced. No SPR or BLI value exists in the literature. The entire E1659A competition scan in Phase 4h is anchored to this number. |
Implication
All dose-occupancy calculations in Phase 4e and all competition scans in Phase 4h inherit this uncertainty. Sensitivity analysis should explicitly include Kd scenarios ranging from 1 nM (strong) to 10 μM (weak) — current Phase 4h already spans this but the WT STRC baseline is fixed at 10 nM without justification.
Actionable next steps
- Request SPR/BLI on STRC × TMEM145 from the Holt, Oliver, or Reimann labs — all three have the reagents and could plausibly add the measurement to a revision. This is the single highest-leverage experiment to validate h03, h09, and h26 at once.
- AF3 ipTM → Kd calibration: run AF3 on pairs with known experimental Kd (positive controls from SKEMPI or PDBbind) to derive an empirical mapping, then reapply to STRC × TMEM145. This is a computational stopgap.
- Include Kd sensitivity in all dose calculations: no single-value claims; report dose × (Kd ∈ {1, 10, 100, 1000, 10000 nM}) matrix.
Cross-hypothesis impact
This gap is not h09-specific:
- h03 (Mini-STRC AAV): transgene product needs to engage TMEM145. Dose-expression model depends on Kd.
- h26 (Engineered Homodimer): avidity design explicitly targets increasing effective Kd against TMEM145. Baseline reference needed.
- h09 (Hydrogel): every Phase 4 number with “occupancy” in it depends on this.
Connections
[part-of]_hub (literature-params)[see-also]2026-04-17-derstroff-tmem145-ohc-stereocilia[see-also]verpy-2011-strc-tm-morphology[see-also]STRC TMEM145 GOLD Domain Interaction[applies]STRC Synthetic Peptide Hydrogel HTC[applies]STRC Mini-STRC Single-Vector Hypothesis[applies]STRC Engineered Homodimer Avidity