Article Dans Une Revue The Journal of clinical investigation Année : 2023

Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding

Yukiko Kurihara
Toru Ekimoto
  • Fonction : Auteur
Yasunobu Uchijima
  • Fonction : Auteur
Ryo Sugiyama
  • Fonction : Auteur
Taro Kitazawa
Akiyasu Iwase
Risa Kotani
  • Fonction : Auteur
Rieko Asai
  • Fonction : Auteur
Véronique Pingault
  • Fonction : Auteur
Mitsunori Ikeguchi
Hiroki Kurihara

Résumé

Mutations of G protein–coupled receptors (GPCRs) cause various human diseases, but the mechanistic details are limited. Here, we establish p.E303K in the gene encoding the endothelin receptor type A (ETAR/EDNRA) as a recurrent mutation causing mandibulofacial dysostosis with alopecia (MFDA), with craniofacial changes similar to those caused by p.Y129F. Mouse models carrying either of these missense mutations exhibited a partial maxillary-to-mandibular transformation, which was rescued by deleting the ligand endothelin 3 (ET3/EDN3). Pharmacological experiments confirmed the causative ETAR mutations as gain of function, dependent on ET3. To elucidate how an amino acid substitution far from the ligand binding site can increase ligand affinity, we used molecular dynamics (MD) simulations. E303 is located at the intracellular end of transmembrane domain 6, and its replacement by a lysine increased flexibility of this portion of the helix, thus favoring G protein binding and leading to G protein–mediated enhancement of agonist affinity. The Y129F mutation located under the ligand binding pocket reduced the sodium-water network, thereby affecting the extracellular portion of helices in favor of ET3 binding. These findings provide insight into the pathogenesis of MFDA and into allosteric mechanisms regulating GPCR function, which may provide the basis for drug design targeting GPCRs.

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hal-04094797 , version 1 (11-05-2023)

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Yukiko Kurihara, Toru Ekimoto, Christopher T Gordon, Yasunobu Uchijima, Ryo Sugiyama, et al.. Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding. The Journal of clinical investigation, 2023, 133 (4), ⟨10.1172/JCI151536⟩. ⟨hal-04094797⟩

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