Your browser doesn't support javascript.
loading
Mutations in LIFR rewire the JAK/STAT signaling pathway: A study unveiling mechanistic details of Stüve-Wiedemann syndrome.
Paul, Ishani; Roy, Alankar; Chakrabarti, Debangana; Nandi, Chandreyee; Ray, Sujay.
Afiliación
  • Paul I; Amity Institute of Biotechnology, Amity University, Kolkata, India.
  • Roy A; Amity Institute of Biotechnology, Amity University, Kolkata, India.
  • Chakrabarti D; Amity Institute of Biotechnology, Amity University, Kolkata, India.
  • Nandi C; Amity Institute of Biotechnology, Amity University, Kolkata, India.
  • Ray S; Amity Institute of Biotechnology, Amity University, Kolkata, India. Electronic address: raysujay@gmail.com.
Comput Biol Med ; 179: 108797, 2024 Sep.
Article en En | MEDLINE | ID: mdl-38968765
ABSTRACT
Stüve-Wiedemann syndrome (SWS), a rare autosomal recessive disorder, characterized by diminutive size, curvature of the elongated bones, bent fingers, episodes of heightened body temperature, respiratory distress or periods of breath-holding, and challenges with feeding, especially causes fatality in infants. SWS is an outcome of potential missense mutations in the leukemia inhibitory factor receptor gene reflected as numerous amino acid mutations at protein level. Employing in silico tools and techniques like mutational screening with Pred_MutHTP, I-Mutant2.0, PANTHER.db, PolyPhen, to classify mutations as deleterious/destabilizing, in conjunction with experimental data analysis, P136A and S279P emerged as 'effect'-causing mutations. Pre-existing knowledge suggests, SWS progression is effectuated conformationally altered and dysfunctional LIFR, unable to bind to LIF and further form the LIF/LIFR/gp130 signalling complex. To gain functional insights into the effect of the said mutations on the wild type protein, an all-atom, explicit, solvent molecular dynamics simulation was performed following docking approaches. Consequently, referring to the RMSD, RMSF, protein dynamic network analysis, energy landscape plots and domain motion analysis, it was revealed that unbound LIFR_WT was more prone to LIF binding as usual whereas the mutants exhibited considerable domain closure to inhibit LIF binding. We conducted binding affinity analysis via MM/GBSA and dissociation constant estimation after LIFR-LIF docking and found the WT_complex to be more stable and compact as a whole when compared to the flexible mutant complexes thus being associated with SWS. Our study offers a route for understanding molecular level implications upon LIFR mutations which opens an avenue for therapeutic interventions.
Asunto(s)
Palabras clave

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Subunidad alfa del Receptor del Factor Inhibidor de Leucemia / Simulación de Dinámica Molecular Límite: Humans Idioma: En Revista: Comput Biol Med Año: 2024 Tipo del documento: Article País de afiliación: India

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Subunidad alfa del Receptor del Factor Inhibidor de Leucemia / Simulación de Dinámica Molecular Límite: Humans Idioma: En Revista: Comput Biol Med Año: 2024 Tipo del documento: Article País de afiliación: India
...