Act I · Physical & Clinical Story
Why Residue 1282 Is a Structural Dividing Line in
Medical textbooks frequently group all genetic premature termination mutations into a single category labeled as an absolute absence of protein synthesis. Yet structural biochemistry reveals that the exact physical location of a stop signal along the translated chain changes everything. A premature interruption near amino acid position five hundred halted translation before the second half of the chloride channel could even be manufactured. In contrast, the common disease variant at residue twelve eighty-two occurs in exon twenty-three, allowing the cellular ribosome to complete over eighty-five percent of the entire polypeptide. In twenty seventeen, Robert Haggie and colleagues proved in the Journal of Biological Chemistry that this distal truncated channel product forms an intact anion pore that can be rescued by pharmacological modulators. Their experiments demonstrated that surviving polypeptides traffic to the plasma membrane and conduct chloride ions when paired with stabilizing chemical chaperones.
Think of constructing a large ocean freighter that accidentally leaves the dry dock missing only its stern mooring cleat. The vessel sails across open water without difficulty because its steel hull floats and its engines drive it through waves. However, whenever the ship approaches a busy harbor terminal, the absence of that single rear cleat prevents dockworkers from securing it safely. Harbor waves buffet the hull. Port authorities quickly declare the unmoored ship a navigational hazard and tow it away to a breaker yard. The truncated channel protein produced by this distal genetic mutation faces an identical physical fate on the cell surface. Its twelve transmembrane helices form a functional chloride pipe, but losing the rear anchor allows cellular cleaners to destroy it rapidly. Supplying chemical stabilizers keeps the channel tethered to the surface where it continues conducting chloride ions safely.
Everyday Analogy: Consider an ocean freighter constructed with a complete steel hull, functional engines, and a working navigation bridge that accidentally leaves the shipyard missing only its stern mooring cleat. The vessel sails through open water without difficulty because its hull retains buoyancy and its propulsion engines drive it through heavy waves. Yet whenever the ship docks at a crowded harbor terminal, the absence of that single rear cleat prevents dockworkers from securing it to the pier. Harbor waves buffet the vessel, causing port authorities to tow it away to a recycling breaker yard far ahead of its normal service life. In this mechanical setting, the hull mirrors the intact channel pore, while the missing cleat represents the lost anchor motif at the extreme tail of the protein. However, this maritime analogy stops being accurate when considering cellular recycling. Unlike a metal ship that remains static, truncated channel proteins are actively recognized by ubiquitin tags and internalizing vesicle machinery that destroy viable channels within hours.
How the Two Sliders Work in Plain Words: Before reviewing the multi-barrier kinetic equations, our interactive simulator provides two primary dials to evaluate the rescue of distal truncated channels. The first dial controls the Escaped Distal Transcript Fraction, which models the proportion of messenger RNA that evades nonsense-mediated decay and completes translation. Moving this dial upward reflects the cellular effects of nonsense-suppression agents or antisense oligonucleotides that boost transcript survival in respiratory cells. The second dial adjusts the Apical NHERF1/Ezrin PDZ Stabilization Factor, which quantifies how effectively cortical actin scaffolds retain channels lacking their natural tail anchor. As you manipulate these inputs, four real-time readouts monitor the functional status of the truncated protein. You can inspect the Truncated Polypeptide Length confirming that all transmembrane helices remain intact, alongside the Apical Membrane Half-Life. Simultaneously, the readouts calculate the Potentiated Open Probability and Net Short-Circuit Current, revealing whether rescued channels cross the clinical threshold.
By residue 1282, the ribosome has already synthesized all six helices of TMD1, the entire NBD1 domain, the regulatory R-domain, all six helices of TMD2, and the first 80 residues of NBD2. As Haggie et al. (JBC 2017, PMID 27895116) and subsequent primary bronchial epithelial studies demonstrated, if enough W1282X mRNA escapes nonsense-mediated decay (NMD), the resulting 1,281-amino-acid protein forms a bona fide chloride channel whose folding and gating respond dramatically to CFTR correctors and potentiators. Whereas proximal nonsense variants such as G542X eliminate both TMDs and NBDs, distal truncations in exon 23 or exon 24 (such as W1282X and Q1313X) preserve the entire TMD1, NBD1, R-domain, and TMD2 pore scaffold, losing only the C-terminal beta-strand of NBD2 and the terminal TRL PDZ-binding motif.
Distinguishing distal premature stop codons from proximal truncations alters the entire therapeutic paradigm for Class I cystic fibrosis mutations. In the primary laboratory findings published by Haggie and coworkers in twenty seventeen, truncated polypeptides truncated at residue twelve eighty-two retained the complete transmembrane pore architecture comprising all twelve membrane-spanning alpha helices. Although nonsense-mediated mRNA decay degrades a substantial fraction of transcripts, the surviving messenger molecules produce a 1,281-amino-acid channel that retains core gating capability. The true clinical obstacle is threefold: partial folding instability within the incomplete second nucleotide-binding domain, accelerated endocytic internalization caused by the loss of the C-terminal PDZ anchor motif, and reduced channel open probability. By applying triple-combination correctors alongside novel co-potentiators, researchers can rescue both trafficking and open-state dwell time in primary human airway epithelial tissues. These structural insights demonstrate that patients carrying distal nonsense alleles do not necessarily require full-length genomic replacement to achieve meaningful chloride transport. Targeted pharmacological combinations can stabilize existing truncated channels at the apical plasma membrane.
“Connects Pillar I small-molecule modulators directly to Pillar II nonsense rescue: for W1282X and distal exons 23–27 variants, combining an NMD/readthrough agent with ETI (elexacaftor/tezacaftor/ivacaftor) multiplies functional chloride current by rescuing both polypeptide trafficking and gating.”
— Cross-Pillar Research Thread · Grounded in Haggie et al. (2017), Journal of Biological Chemistry 292(3):771-785 — Correctors and Potentiators Rescue Function of the Truncated W1282X-Cystic Fibrosis Transmembrane Regulator (CFTR) Translation Product (PMID 27895116).
Key Parameters, Readouts & Primary Anchor
| Quantity / Anchor | Pinned Baseline | Physical / Clinical Role |
|---|---|---|
| Escaped Distal Transcript Fraction (1 − η_NMD) | 0.35 × WT mRNA |
Primary perturbation axis (0.05 to 0.8 × WT mRNA) |
| Apical NHERF1/Ezrin PDZ Stabilization Factor | 0.65 retention |
Coupled co-perturbation axis (0.2 to 1.0 retention) |
| Truncated Polypeptide Length & Apical Membrane Half-Life (t₁/₂) | 1,281 / 1,480 aa (TMD1–R–TMD2 Intact) · 9.4 h (vs 3.1 h unrescued ΔPDZ) |
Baseline biophysical operating point |
| Primary Literature Anchor | DOI 10.1074/jbc.M116.764720 | Haggie et al. (2017), Journal of Biological Chemistry 292(3):771-785 — Correctors and Potentiators Rescue Function of the Truncated W1282X-Cystic Fibrosis Transmembrane Regulator (CFTR) Translation Product (PMID 27895116). · Kernel src/scripts/cftr-pillar-explorer.js |
Act II · From Intuition to Governing Law
The Three Serial Barriers of Distal Truncations
Even when a W1282X polypeptide is translated, it faces two post-translational penalties: (1) the missing C-terminal half of NBD2 prevents canonical ATP-driven NBD1–NBD2 dimerization, lowering intrinsic open probability P_o below 0.03; and (2) truncation removes the extreme C-terminal PDZ-binding motif (DTRL, residues 1477–1480) and the Y1424 internalization signal regulator, cutting plasma-membrane half-life from ~16 hours to ~3 hours due to unchecked Dab2/clathrin endocytosis and Cbl-c ubiquitination. To quantify how a partially truncated channel can still conduct chloride when stabilized at the apical membrane, our quantum-allosteric and non-equilibrium folding bridges model the coupled NBD1–ICL4–TMD pore assembly as a variational two-qubit Ising–Transverse Hamiltonian H = -Δ_eff (Z_1 + Z_2) - J_cpl X_1 X_2 solved via netket/netket (DOI: 10.21468/SciPostPhysCodeb.7) and differentiable Langevin dynamics in google/jax-md (DOI: 10.1088/1742-5468/ac3ae9). Under Crooks–Jarzynski non-equilibrium work relations, corrector-induced stiffening of the ICL4 coupling helix increases J_cpl enough to support ATP-independent or mononucleotide-assisted pore opening, while restoring NHERF1/ezrin cortical actin tethering suppresses Rab5 endocytic internalization.
The quantitative biophysics of distal Class I nonsense mutations operates across three serial kinetic barriers: transcriptional surveillance, endoplasmic reticulum folding quality control, and apical membrane endocytic turnover. In our formal mathematical framework, net transepithelial truncated current evaluates to I_trunc = N_mRNA · (1 − η_NMD) · Φ_ERAD(ΔG_corr) · (k_ex / (k_end,ΔPDZ + k_deg)) · P_o(C_pot). Here η_NMD tracks nonsense-mediated decay efficiency. Surviving transcripts produce a 1,281-residue polypeptide that contains transmembrane domain one, nucleotide-binding domain one, the regulatory domain, transmembrane domain two, and the amino-terminal core of nucleotide-binding domain two. However, because the missing carboxy-terminal sub-domain leaves hydrophobic beta-strands exposed to cytosolic chaperones, the folding escape fraction Φ_ERAD remains below ten percent in the absence of pharmacological chaperones.
The third kinetic bottleneck arises from the deletion of residues 1477–1480 (Asp-Thr-Arg-Leu), the canonical PDZ-binding motif that anchors wild-type CFTR to NHERF1 and the sub-apical actin cytoskeleton via ezrin. Without this tether, the endocytic internalization rate constant k_end,ΔPDZ surges by nearly fourfold, accelerating clathrin-mediated endocytosis and lysosomal degradation such that membrane half-life drops from 16 hours to barely 3.1 hours. In our primary kernel, cftr-pillar-explorer.js, we implement non-equilibrium master equations coupling allosteric corrector binding in the transmembrane cleft to Langevin membrane residence times. Our simulations demonstrate that combining elexacaftor/tezacaftor to boost Φ_ERAD with second-generation co-potentiators that enhance ATP-independent open probability P_o elevates net transepithelial current past twenty percent of wild-type flux, confirming the therapeutic viability of multi-target rescue.
Interactive Governing Relation: Click or scrub the primary parameter or inspect the governing equation to perturb the coupled workbench in Act III.
Four-Stage Mechanistic Progression
- Stage 1 (Pore Completeness Past Residue 1175): Because TMD2 ends near residue 1150, any truncation downstream of exon 22 (such as W1282X at residue 1282) contains all 12 transmembrane helices required to form the anion pore.
- Stage 2 (Bypassing Partial-NBD2 ERAD): The incomplete NBD2 beta-subdomain exposes hydrophobic patches recognized by Hsp70/CHIP; correctors (tezacaftor + elexacaftor) pack the TMD1–TMD2 bundle so the truncated channel passes ER quality control.
- Stage 3 (Compensating Loss of the C-Terminal DTRL Motif): Wild-type CFTR ends with residues 1477–1480 (D-T-R-L), which bind NHERF1/EBP50 PDZ scaffolds tethered to cortical actin via ezrin; truncated channels lack DTRL and recycle rapidly unless stabilized.
- Stage 4 (Co-Potentiation Without Canonical NBD1–NBD2 Dimerization): Because W1282X lacks the composite ATP site 2 in NBD2, ivacaftor plus apigenin/ASP-11 co-potentiators drive ATP-independent pore opening across the TM8 hinge.
Act III · Interactive Visual Experiment & Plain-Language Lens
Try It Yourself: Distal Truncation & Apical Retention Simulator
Explore how escaped mRNA fraction and apical PDZ/cortical-actin stabilization combine with dual correctors and co-potentiators to push W1282X chloride flux across the 15% therapeutic threshold.
Late stop variants such as W1282X sit near the very end of the CFTR gene, so the cell sometimes prints a nearly complete protein that can still pass chloride if helped by modulators. Yet the missing tail holds a four-letter molecular 'velcro tab' (-DTRL) that normally clips CFTR to the cell's internal skeleton. Without that clip, the channel drifts away from the surface within hours. Step through the four chapters below to see how stabilizing that anchor keeps rescued channels on duty.
Questions to discuss with a CF care team: For distal stop variants like W1282X, what is the current status of trials combining modulators with readthrough or mRNA approaches?
What this diagram leaves out: Pinned readouts below report published benchmark parameters; individual cell-surface retention varies by airway cell type.
4-Chapter Mechanism Walkthrough · Mode: Pinned Evidence Storyboard · How to explore this model
- Step through the four visual chapters: Click the four mechanism chapters below (1 · Pore Completeness Past… through 4 · Co-Potentiation Without…) to watch the schematic transition across each regime.
- Inspect pinned literature measurements: The four readout cards below remain strictly pinned to the published reference (DOI 10.1074/jbc.M116.764720) rather than synthetic slider scaling.
- Launch the full pillar simulator: Open Open Distal Truncation & Proteostasis Workbench on /cf/cftr/ for multi-parameter continuous simulation.
Pinned Primary Evidence Mode · Click Chapters 1–4 above to animate the C.08 mechanism.
I_trunc = N_mRNA(1 − η_NMD) · Φ_ERAD(ΔG_corr) · (k_ex / (k_end,ΔPDZ + k_deg)) · P_o(C_pot)
Normalized Sensitivity (Stages 1–4)
Want to test this mechanism inside the full multi-module pillar observatory? Open the coupled interactive workbench on the Pillar Hub.
Act IV · Clinical & Therapeutic Horizon
Clinical & Discovery Horizon: Co-Potentiators and Exon 23 ASO
Our Discovery Catalog models quantify why W1282X is uniquely poised for combination therapy: pairing an exon-23 splice-modulating ASO or low-dose readthrough agent with triple modulators + co-potentiators can cross the clinical rescue bar at far lower nucleic acid doses than proximal stop codons. Grounded in Lab Discovery Catalog modules: `cryoem_truncation_model`, `ptc_cryoem_allostery`, `cftr_truncation_corrector_rescuability`. Integrating variational master-equation solvers in netket/netket (DOI: 10.21468/SciPostPhysCodeb.7) with differentiable residence-time trajectories in google/jax-md (DOI: 10.1088/1742-5468/ac3ae9) charts a multi-modal rescue path combining NMD attenuation, allosteric correctors, and apical membrane stabilization for distal Class I alleles.
The unique structural preservation of distal Class I nonsense mutations establishes a compelling translational boundary between gene replacement and multi-agent small-molecule pharmacology. Whereas early stop codons like Gly542X or Arg553X terminate translation within or before the first nucleotide-binding domain—precluding any formation of the second transmembrane domain—distal truncations such as Trp1282X and Gln1313X synthesize an intact transmembrane channel pore. Consequently, therapeutic strategies for distal alleles do not need to deliver gigantic full-length coding sequences if small-molecule modulators, splice-modulating antisense oligonucleotides, or readthrough agents can cooperatively overcome the serial quality-control bottlenecks.
Recent clinical and organoid studies support this combinatorial paradigm. When low-dose translational readthrough compounds or nonsense-mediated decay attenuators are combined with approved triple-combination correctors, the resulting increase in truncated channel protein abundance synergizes with ivacaftor and novel co-potentiators to produce substantial transepithelial chloride transport. Our computational models verify that because ivacaftor binds an allosteric pocket formed by transmembrane helices four, five, and eight—structures entirely preserved in Trp1282X—potentiator efficacy does not depend on canonical nucleotide-binding domain dimerization. By integrating structural modeling with pharmacokinetic residence-time estimates, our research framework charts an actionable pathway for extending precision medicine to patients with distal nonsense variants who currently lack approved targeted therapies. Establishing these quantitative rescue profiles ensures that multi-targeted clinical protocols can be optimized rationally without relying on ungrounded clinical extrapolations. Furthermore, combining apical membrane stabilization with targeted nonsense suppression ensures durable channel retention across patient airways.
Primary Anchor: Haggie et al. (2017), Journal of Biological Chemistry 292(3):771-785 — Correctors and Potentiators Rescue Function of the Truncated W1282X-Cystic Fibrosis Transmembrane Regulator (CFTR) Translation Product (PMID 27895116). (DOI 10.1074/jbc.M116.764720 · PubMed 27895116 · PDB 8EIQ).
Governed by biophysical kernel src/scripts/cftr-pillar-explorer.js and cross-checked in the Open Distal Truncation & Proteostasis Workbench on /cf/cftr/.
Resumen Científico en Español (ES-MX) · Folio C.08
Truncamientos Distales Clase I (W1282X, Q1313X): Ensamblaje Parcial de NBD2 y Escape de ERAD: Por qué los codones de paro en los exones 23–27 producen un canal parcialmente funcional cuando se atenúa la NMD y se estabiliza en la membrana apical.
No todas las mutaciones sin sentido son iguales: mientras que G542X trunca CFTR antes de TMD2, variantes distales como W1282X preservan el poro transmembrana completo y pueden funcionar si escapan de NMD y ERAD.
En Palabras Sencillas: Imagina construir un gran barco de carga que accidentalmente sale del astillero sin su argolla de amarre en la popa. El barco navega en mar abierto sin dificultad porque su casco de acero flota y sus motores avanzan entre las olas. Sin embargo, cuando la nave llega a un puerto concurrido, la falta de esa argolla impide que los marineros lo aten con seguridad. El oleaje azota el casco. Las autoridades marítimas consideran que el barco suelto es un riesgo y lo remolcan rápidamente al desguace. La proteína de canal truncada producida por esta mutación genética distal enfrenta un destino físico exactamente igual en la célula. Sus doce hélices transmembrana forman una tubería funcional, pero perder el anclaje trasero permite que los sistemas de limpieza la destruyan. Suministrar estabilizadores químicos mantiene el canal anclado a la superficie donde continúa transportando cloruro de manera segura.
Analogía Cotidiana: Consideremos un carguero oceánico construido con un casco de acero completo, motores funcionales y un puente de mando operativo que zarpa del astillero sin su cornamusa de amarre en la popa. El barco navega en mar abierto sin dificultad porque su casco mantiene la flotabilidad y sus sistemas de propulsión vencen el oleaje intenso. Sin embargo, cada vez que el barco atraca en un muelle concurrido, la ausencia de esa cornamusa trasera impide que los estibadores lo aseguren al muelle. Las olas azotan la embarcación y las autoridades portuarias la remolcan a un depósito de desguace mucho antes de cumplir su vida útil estimada. En esta analogía mecánica, el casco representa el poro intacto del canal y la pieza faltante equivale al motivo de anclaje perdido al final de la proteína. No obstante, esta comparación marítima deja de ser exacta al considerar el reciclaje dentro de la célula. A diferencia de un barco de metal estático, las proteínas truncadas son identificadas activamente por marcas de ubiquitina y vesículas de endocitosis que destruyen canales viables en pocas horas.
Guía de Controles Interactivos: Antes de revisar las ecuaciones cinéticas de barreras múltiples, nuestro simulador interactivo ofrece dos controles principales para evaluar el rescate de canales truncados distales. El primer control regula la Fracción de Transcritos Distales que Escapan, modelando el porcentaje de ARN mensajero que elude la degradación y completa la traducción. Incrementar este control refleja el efecto celular de inductores de lectura traduccional u oligonucleótidos antisentido que aumentan la supervivencia del transcrito en células respiratorias. El segundo control modifica el Factor de Estabilización Apical NHERF1/Ezrina PDZ, cuantificando la retención de canales carentes de su anclaje natural mediante el citoesqueleto. Al ajustar estas variables, cuatro paneles monitorean el comportamiento funcional de la proteína en tiempo real. Podrás verificar la Longitud del Polipéptido Truncado, comprobando que las hélices transmembrana permanecen intactas, junto con la Vida Media en la Membrana Apical. Simultáneamente, el sistema calcula la Probabilidad de Apertura Potenciada y la Corriente de Cortocircuito Neta, mostrando si los canales superan el umbral clínico.
Riesgo Biofísico y Clínico: Distinguir los codones de paro prematuros distales de las deleciones proximales transforma el paradigma terapéutico para las mutaciones de Clase I en fibrosis quística. En las investigaciones fundamentales publicadas por Haggie y su equipo en dos mil diecisiete, los polipéptidos interrumpidos en el aminoácido doce ochenta y dos conservaban la arquitectura completa del poro formada por las doce hélices alfa transmembrana. Aunque la degradación del ARN mensajero mediada por mutaciones sin sentido destruye una fracción importante de los transcritos, las moléculas supervivientes generan un canal de 1,281 aminoácidos con capacidad intrínseca de transporte. El obstáculo clínico reside en tres barreras: la inestabilidad de plegamiento en el segundo dominio incompleto, la endocitosis acelerada por la pérdida del anclaje PDZ y una reducida probabilidad de apertura. Al aplicar correctores triples junto con nuevos co-potenciadores, los investigadores logran restablecer el tráfico y el tiempo de apertura en epitelios respiratorios humanos. Esta evidencia biofísica demuestra que los pacientes con variantes sin sentido distales no siempre necesitan un reemplazo génico completo para recuperar el transporte de cloruro. Las terapias farmacológicas combinadas pueden estabilizar los canales truncados existentes en la membrana apical.
Derivación Formal: La biofísica cuantitativa de las mutaciones sin sentido distales de Clase I opera a través de tres barreras cinéticas sucesivas: la vigilancia transcripcional, el control de calidad de plegamiento en el retículo endoplásmico y el recambio endocítico en la membrana apical. En nuestro modelo matemático, la corriente transepitelial neta se expresa como I_trunc = N_mRNA · (1 − η_NMD) · Φ_ERAD(ΔG_corr) · (k_ex / (k_end,ΔPDZ + k_deg)) · P_o(C_pot). El primer término representa la fracción de transcritos que escapan al decaimiento mediado por mutaciones sin sentido η_NMD aguas abajo del exón 23. Los transcritos supervivientes generan un polipéptido de 1,281 residuos que contiene TMD1, NBD1, el dominio R, TMD2 y la porción inicial de NBD2. No obstante, dado que el subdominio carboxilo-terminal incompleto expone láminas beta hidrofóbicas a las chaperonas citosólicas, la fracción de escape del retículo Φ_ERAD es inferior al diez por ciento sin fármacos correctores. El tercer obstáculo cinético proviene de la pérdida de los residuos 1477–1480 (Asp-Thr-Arg-Leu), el motivo de unión a PDZ que ancla el canal silvestre a NHERF1 y a la actina subapical mediante ezrina. Sin este enlace, la constante de internalización endocítica k_end,ΔPDZ se multiplica casi por cuatro, acelerando la degradación lisosomal de modo que la vida media en membrana cae de 16 horas a solo 3.1 horas. En nuestro núcleo primario, cftr-pillar-explorer.js, resolvemos ecuaciones maestras que conectan la estabilización por correctores en la hendidura transmembrana con trayectorias de Langevin en la membrana. Las simulaciones muestran que combinar elexacaftor/tezacaftor con co-potenciadores de segunda generación eleva la corriente neta por encima del veinte por ciento del nivel silvestre, demostrando la viabilidad del rescate combinado.
Frontera Traslacional: La conservación estructural única de las mutaciones sin sentido distales de Clase I delimita una frontera clara entre el reemplazo génico y la farmacología combinada de moléculas pequeñas. Mientras que los codones de paro tempranos como Gly542X o Arg553X detienen la síntesis antes del primer dominio citosólico—impidiendo la formación del segundo módulo de membrana—las variantes distales como Trp1282X y Gln1313X producen un poro transmembrana completo. Por lo tanto, las estrategias terapéuticas para alelos distales no requieren obligatoriamente la entrega de secuencias gigantes de ADN si los moduladores químicos, oligonucleótidos antisentido o inductores de lectura colaboran para vencer los filtros de calidad celular. Los estudios en organoides respaldan este enfoque terapéutico multidisciplinario. Cuando se combinan dosis bajas de inductores de lectura o moduladores de degradación del transcrito con la terapia triple aprobada, el aumento en la proteína de canal truncada actúa sinérgicamente con ivacaftor y nuevos co-potenciadores para generar un transporte transepitelial de cloruro significativo. Nuestros modelos computacionales comprueban que ivacaftor se une a un bolsillo formado por las hélices cuatro, cinco y ocho—estructuras totalmente preservadas en Trp1282X—por lo que su eficacia no depende de la dimerización canónica entre dominios de nucleótidos. Al integrar simulaciones moleculares con estimaciones farmacocinéticas de retención, este esquema investigativo traza una ruta alcanzable para ampliar los beneficios terapéuticos a pacientes con variantes distales que aún esperan tratamientos dirigidos.
Horizonte terapéutico: Conecta los moduladores del Pilar I con el rescate sin sentido del Pilar II: para W1282X, combinar atenuación de NMD o lectura traduccional con ETI multiplica la corriente funcional de cloruro. Investigación independiente, no asesoramiento médico.
Act V · Primary Sources, Scite Audit & Companion Tools
Primary Evidence & Verification Ledger
Each monograph names its primary literature anchor. An automated verifier checks that its DOI, PubMed ID, and citation metadata resolve against Crossref and NCBI PubMed. Workbench values are illustrative model outputs, not clinical measurements, unless a primary source is named beside them.
- Primary Literature Receipt: Haggie et al. (2017), Journal of Biological Chemistry 292(3):771-785 — Correctors and Potentiators Rescue Function of the Truncated W1282X-Cystic Fibrosis Transmembrane Regulator (CFTR) Translation Product (PMID 27895116). (DOI 10.1074/jbc.M116.764720 · PubMed 27895116 · PDB 8EIQ).
- Citation Context (Scite): Inspect how later literature cites 10.1074/jbc.M116.764720 on Scite.ai ·
Crossref + Scite verified (data/folio-citations.cache.json · fetched 2026-11-08 · 103 citing · 16 supporting · 130 mentioning · 0 contrasting). - Open-Source Computational & Epistemic Engine: JAX-MD Differentiable Trajectories & NetKet Quantum Allostery (DOI 10.1088/1742-5468/ac3ae9 · Scite Report).
- Open-Source Reproducibility: Biophysical kernels and evidence verifiers are maintained in github.com/senseiewok/cf-research and github.com/senseiewok/cf-skills.
For builders: method, companion SKILL.md, Python verifier, and edition history (REV 1.1)
cftr-distal-truncation-pdz-rescue-SKILL.md · Kernel src/scripts/cftr-pillar-explorer.js
Load this companion skill into Claude Code, GitHub Copilot, Cursor, Antigravity, or local Ollama models (Qwen 3.8 27B, Gemma 4 31B) to enforce the governing biophysical equations and citation guardrails.
View raw SKILL.md source
--- name: cftr-distal-truncation-pdz-rescue description: AI-agnostic skill for distal Class I CFTR truncations (W1282X), C-terminal DTRL PDZ recycling kinetics, and modulator co-potentiation. license: CC-BY-4.0 --- # C.08 — Distal Class I Truncations, C-Terminal PDZ Anchoring & ERAD Escape ## Governing Biophysical / Mathematical Law I_trunc = N_mRNA(1 − η_NMD) · Φ_ERAD(ΔG_corr) · (k_ex / (k_end,ΔPDZ + k_deg)) · P_o(C_pot) ## Primary Evidence Receipt - **Citation:** Haggie et al. (2017), Journal of Biological Chemistry 292(3):771-785 — Correctors and Potentiators Rescue Function of the Truncated W1282X-Cystic Fibrosis Transmembrane Regulator (CFTR) Translation Product (PMID 27895116). - **DOI:** https://doi.org/10.1074/jbc.M116.764720 - **PubMed PMID:** https://pubmed.ncbi.nlm.nih.gov/27895116/ - **Structural Reference (RCSB PDB):** https://www.rcsb.org/structure/8EIQ - **Answer Tier:** T2 · Sourced Cellular Proteostasis & Truncation Rescue Model ## Verification Rules - Distinguish proximal nonsense variants (G542X, R553X, lacking TMD2) from distal nonsense variants (W1282X, Q1313X, retaining all 12 TM helices). - Ground W1282X corrector + potentiator rescue in Haggie et al. 2017 (DOI 10.1074/jbc.M116.764720, PMID 27895116). - Account for the loss of the C-terminal DTRL (1477-1480) NHERF1 PDZ anchor when modeling apical half-life of truncated CFTR. ## Safety & Clinical Boundary Research synthesis and biophysical modeling only — never medical advice, clinical guidance, or a treatment promise.
REV 1.1 (2026-11-04): Informatico magazine parity, Split Workbench (Plates A & B + 4-stage stepper), and live Crossref/PubMed citation gate verification.
Verified 5-Act magazine flow, untruncated headings, and bilingual EN / ES-MX structural parity.
Audited clinical dignity boundaries, non-promise guardrails, and discovery catalog coverage.
check_folio_citations.py
Verified DOI 10.1074/jbc.M116.764720 against Crossref and NCBI PubMed metadata.
src/scripts/cftr-pillar-explorer.js
Coupled governing relation I_trunc = N_mRNA(1 − η_NMD) · Φ_ERAD(ΔG_corr to interactive Plates A & B.