Computational analysis of long-range allosteric communications in CFTR

Author:

Ersoy Ayca12,Altintel Bengi12,Livnat Levanon Nurit3,Ben-Tal Nir4ORCID,Haliloglu Turkan12,Lewinson Oded3ORCID

Affiliation:

1. Department of Chemical Engineering, Bogazici University

2. Polymer Research Center, Bogazici University

3. Department of Molecular Microbiology, Bruce and Ruth Rappaport Faculty of Medicine, Technion-Israel Institute of Technology

4. Department of Biochemistry and Molecular Biology, Faculty of Life Sciences, Tel-Aviv University

Abstract

Malfunction of the CFTR protein results in cystic fibrosis, one of the most common hereditary diseases. CFTR functions as an anion channel, the gating of which is controlled by long-range allosteric communications. Allostery also has direct bearings on CF treatment: the most effective CFTR drugs modulate its activity allosterically. Herein, we integrated Gaussian network model, transfer entropy, and anisotropic normal mode-Langevin dynamics and investigated the allosteric communications network of CFTR. The results are in remarkable agreement with experimental observations and mutational analysis and provide extensive novel insight. We identified residues that serve as pivotal allosteric sources and transducers, many of which correspond to disease-causing mutations. We find that in the ATP-free form, dynamic fluctuations of the residues that comprise the ATP-binding sites facilitate the initial binding of the nucleotide. Subsequent binding of ATP then brings to the fore and focuses on dynamic fluctuations that were present in a latent and diffuse form in the absence of ATP. We demonstrate that drugs that potentiate CFTR’s conductance do so not by directly acting on the gating residues, but rather by mimicking the allosteric signal sent by the ATP-binding sites. We have also uncovered a previously undiscovered allosteric ‘hotspot’ located proximal to the docking site of the phosphorylated regulatory (R) domain, thereby establishing a molecular foundation for its phosphorylation-dependent excitatory role. This study unveils the molecular underpinnings of allosteric connectivity within CFTR and highlights a novel allosteric ‘hotspot’ that could serve as a promising target for the development of novel therapeutic interventions.

Funder

North Atlantic Treaty Organization

Israel Academy of Sciences and Humanities

Scientific and Technological Research Council of Turkey

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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