STRC TMEM145 GOLD Domain Interaction
AlphaFold 3 predicts a direct protein-protein interaction between the mini-STRC construct (residues 700–1775) and the GOLD domain of TMEM145.
Key result
- ipTM = 0.74 — confident predicted interaction (threshold: >0.6 = likely real)
- Interacting regions: mini-STRC (700–1775) × TMEM145 GOLD domain
- Interface context: TMEM145 is expressed in OHC stereocilia; this interaction suggests mini-STRC is functionally embedded in the stereocilia scaffold
Significance
Derstroff et al. 2026 identified TMEM145 as a novel OHC stereocilia protein. If mini-STRC (the gene therapy construct) retains this interface, the truncated protein can still participate in normal stereocilia organization — a key safety/efficacy signal.
Connection to RBM24 splicing (revised 2026-04-20)
Interface residues extracted from AF3 Job 2 CIF (atom-atom < 5 Å) cluster at STRC aa 1603–1770 (C-terminal ARM repeats), not ~950–1200 as earlier estimated. See STRC RBM24 Exon Mapping to Human Protein for method and full data.
None of the 4 RBM24-regulated STRC exons overlap this interface directly:
- E1 (1047–1102): 501 aa upstream
- E2/E4 (1311–1376): 227 aa upstream
- E3 (712–732): 871 aa upstream
Direct “RBM24 → E1 skipping → TMEM145 anchor broken” mechanism is not supported. Possible indirect mechanisms remaining: (1) allosteric destabilization of ARM-repeat fold on ΔE1, (2) scaffold-geometry change, (3) E1 serves a different function. Testable with AF3 ΔE1 jobs (queued).
Interface residues (from AF3 Job 2 CIF, 2026-04-20)
Six contact clusters in STRC (all in C-terminal ARM repeats):
- 1603–1607 (5 res)
- 1630–1638 (9 res)
- 1648–1651 (4 res)
- 1669–1680 (12 res)
- 1692–1707 (16 res)
- 1770 (C-terminus, 1 res)
32 unique STRC interface residues total, 26 TMEM145 interface residues. Computed via Biopython + 5 Å atom-atom cutoff on job2-mini-complex.cif. Data: ~/STRC/models/strc_tmem145_interface_from_cif.json.
Remaining question: confirm with a Derstroff-style pruned (GOLD-only) AF3 job, expected ipTM > 0.7.
Connections
[source]2026-04-17-derstroff-tmem145-ohc-stereocilia — TMEM145 paper providing the interacting partner[supports]STRC Mini-STRC Single-Vector Hypothesis — mini-STRC retains key protein interactions- STRC RBM24 Exon Mapping to Human Protein — E1 (RBM24-regulated, 56 aa) overlaps this interface at aa 1047–1102
[see-also]STRC RBM24 Exon Splicing Quantification — upstream quantitative data[part-of]STRC AlphaFold3 Computational Experiments — part of AF3 analysis campaign[about]Jeffrey Holt — co-author of Derstroff et al. 2026