STRC Research

Derstroff et al 2026 TMEM145 Paper

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Derstroff et al. 2026 — TMEM145 is a principal component of outer hair cell stereocilia

Citation

Derstroff D, Flook M, Lohnes A, Kreye P, Newton S, Renigunta V, Hanemaaijer S, Aguilar C, Holt JR, Bowl MR, Oliver D, Reimann K. “TMEM145 is a principal component of outer hair cell stereocilia.” Neuron 114, 1-15, August 5, 2026. DOI: 10.1016/j.neuron.2026.03.007

Authors & Affiliations

  • Dennis Derstroff, Antonia Lohnes, Paulina Kreye — Philipps-University Marburg (ORL dept)
  • Marisa Flook, Sherylanne Newton — UCL Ear Institute / MRC Harwell
  • Jeffrey R. Holt — Boston Children’s Hospital / Harvard Medical School (co-author)
  • Michael R. Bowl — UCL Ear Institute (corresponding)
  • Katrin Reimann — Philipps-University Marburg (corresponding, lead contact)

Key Discovery

TMEM145 is the missing transmembrane core component of TM-ACs (tectorial membrane attachment crowns) and HTCs (horizontal top connectors) in OHC stereocilia. It forms a ternary complex:

Tubby (intracellular) → TMEM145 (transmembrane) → STRC (extracellular) → TM

Architecture of the Complex

  • TMEM145 is a GOST-family protein (GPCR-related, 7-transmembrane, extracellular GOLD domain)
  • Tubby binds to TMEM145’s cytosolic C-terminus (via tubby domain, facilitated by PI(4,5)P2)
  • STRC binds to TMEM145’s extracellular GOLD domain via C-terminal armadillo repeats
  • STED super-resolution: ring diameters 198 nm (tubby) < 224 nm (TMEM145) < 269 nm (STRC)

STRC Binding Site on TMEM145 — CRITICAL FOR MINI-STRC

STRC binds via its C-TERMINAL region (aa ~700-1780)

  • AF3 predicted association of STRC with GOLD domain via C-terminal armadillo repeat
  • Full-length STRC + GOLD domain: ipTM = 0.71
  • Pruned fragments (isolated GOLD + ARM repeats): ipTM up to 0.91 (high confidence)
  • Interface was invariant across all fragment combinations tested
  • N-terminal STRC (aa 1-720) showed NO interaction with TMEM145 (ipTM < 0.23)
  • Intermediate region (aa 500-1250) also no binding to TMEM145

Experimental confirmation (coIP)

  • Deletion of GOLD domain from TMEM145 abolished STRC binding (coIP)
  • STRC was pulled down with FLAG-tagged TMEM145 in HEK cells
  • Binding is extracellular (GOLD domain of TMEM145)

Implications for Mini-STRC Hypothesis

GOOD NEWS: Mini-STRC preserves the TMEM145 binding site

All mini-STRC constructs preserve the C-terminal armadillo repeats:

  • Mini-STRC (616-1775): preserves entire binding region
  • Shorter mini-STRC (700-1775): preserves entire binding region (ipTM 0.91 region starts ~700+)
  • C-term only (1075-1775): still preserves the ARM repeats used in binding

The N-terminal region we remove (aa 1-615/700) has NO interaction with TMEM145 (ipTM < 0.23). This is now confirmed by both:

  1. Our AF3 computational predictions (ipTM 0.43-0.47 for full constructs)
  2. Derstroff et al.’s independent AF3 + coIP validation

NEW REQUIREMENT: TMEM145 must be present for STRC function

  • Without TMEM145, STRC cannot reach stereocilia tips
  • Without TMEM145, tubby is also absent
  • The complex is mutually dependent: loss of any component = loss of all
  • Mini-STRC gene therapy only works if the patient’s TMEM145 is functional

For DFNB16 patients (STRC mutations)

  • TMEM145 gene is typically intact in DFNB16 patients
  • The therapy replaces only STRC (the broken gene)
  • TMEM145 is already there, waiting for its binding partner
  • Mini-STRC should bind TMEM145 via C-terminal ARM repeats just like full-length

Knockout Phenotype (Tmem145 KO mice)

  • Profound hearing loss (~50 dB SPL elevation across all frequencies)
  • Loss of DPOAEs (no cochlear amplification)
  • Early onset, non-progressive (present at 3 weeks)
  • Progressive hair bundle degeneration (3mo: disorganized, 5mo: substantial, 12mo: mostly absent)
  • IHC hair bundles unaffected (TMEM145 is OHC-specific)
  • MET channels (tip-links, CDH23, LHFPL5) normal and functional

Other Findings

  • TMEM145 localizes to tips of tallest stereocilia row (ring-like pattern by STED)
  • Traffics to apical membrane and primary cilia in polarized epithelial cells
  • Tubby enhances TMEM145 trafficking to plasma membrane
  • PI(4,5)P2 depletion displaces tubby from stereocilia but TMEM145 remains
  • Developmental: TMEM145 appears at TM-ACs ~P5-P7, HTCs ~P12

Therapeutic Window Note (from Discussion)

“The anatomically and functionally preserved cochlear environment observed in the absence of Tmem145 may offer a critical therapeutic window for future interventions.”

PDF Location

~/Documents/Derstroff et al 2026.pdf

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