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Respiratory

Possiblity Of New Treatments For Cystic Fibrosis-1

4 months, 1 week ago

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Posted on Jan 13, 2018, 4 a.m.

Cryo-electron microscopy has successfully been used by biochemists at the University of Zurich to decrypt the architecture of the chloride channel TMEM16A, in which the protein structure of could prove to be helpful to unlocking the development of drugs to treat cystic fibrosis.

Cryo-electron microscopy has successfully been used by biochemists at the University of Zurich to decrypt the architecture of the chloride channel TMEM16A, in which the protein structure of could prove to be helpful to unlocking the development of drugs to treat cystic fibrosis.

 

Cystic fibrosis is a hereditary disease of the lungs, which currently there is no cure for. Underlying cause of cystic fibrosis is the malfunction of the chloride channel CFTR. This malfunction prevents the secretion of chloride in certain cells, which then leads to dehydration of the lung mucus layer. Activation of the calcium activated chloride channel TMEM16A to be used as an alternative route for chloride efflux holds promise in treating the severe disease since CFTR is expressed in the same epithelium as TMEM16A, and the activation may restore lung mucus layer hydration.

 

TMEM16A belongs to a protein family which facilitates the flow of negatively charged chloride lipids or ions across cell membrane. Structure of its scramblase, was known from previous work, that functions as a lipid transporter and helps in blood coagulation. Cryo-electron microscopy, successfully led by Professor Raymond Dutzler, has been used to decrypt the architecture of the chloride channel TMEM16A.

 

TMEM16A can be found in various organs in the body which play roles in the contraction of smooth muscles, the perception of pain, and the secretion of chloride in the lung. Just how the protein becomes activated by calcium has become decrypted through a combination of electrophysiology and cryo-EM, and how its structure is different from other closely related scramblases within the same family. In general it resembles other scramblases within the same family, having distinctive differences in the pore region, which is located within each subunit of the dimeric protein. Scramblases contain membrane exposed polar furrow that allows diffusion of lipid headgroups across lipid bilayer. TMEM16A will, in contrast, at that same location form an hourglass shaped protein enclosed channel that is closed in the absence of calcium. Binding of positively charged calcium ions opens the channel to allow negatively charged chloride ions to permeate across the membrane.

 

Because of the bound calcium ions directly changing electrostatics and structure of the ion permeation pores, this makes this a unique activation mechanism, according to Cristina Paulino. These findings of TMEM16A may open the way for a mechanism understanding the importance of this family of membrane proteins which may provide a template to utilize in the development of drugs for the treatment of cystic fibrosis.

 

 

 

Materials provided by University of Zurich.

Note: Content may be edited for style and length.

Journal Reference:

Cristina Paulino, Valeria Kalienkova, Andy K. M. Lam, Yvonne Neldner, Raimund Dutzler. Activation mechanism of the calcium-activated chloride channel TMEM16A revealed by cryo-EM. Nature, 2017; DOI: 10.1038/nature24652

 

 

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