TY  - JOUR
AU  - Dos Santos Morais, Raphael
AU  - Delalande, Olivier
AU  - Pérez, Javier
AU  - Mias-Lucquin, Dominique
AU  - Lagarrigue, Mélanie
AU  - Martel, Anne
AU  - Molza, Anne-Elisabeth
AU  - Chéron, Angélique
AU  - Raguénès-Nicol, Céline
AU  - Chenuel, Thomas
AU  - Bondon, Arnaud
AU  - Appavou, Marie-Sousai
AU  - Le Rumeur, Elisabeth
AU  - Combet, Sophie
AU  - Hubert, Jean-François
TI  - Human Dystrophin Structural Changes upon Binding to Anionic Membrane Lipids
JO  - Biophysical journal
VL  - 115
IS  - 7
SN  - 0006-3495
CY  - Bethesda, Md.
PB  - Soc.
M1  - FZJ-2018-06069
SP  - 1231 - 1239
PY  - 2018
AB  - Scaffolding proteins play important roles in supporting the plasma membrane (sarcolemma) of muscle cells.Among them, dystrophin strengthens the sarcolemma through protein-lipid interactions, and its absence due to gene mutationsleads to the severe Duchenne muscular dystrophy. Most of the dystrophin protein consists of a central domain made of 24 spec-trin-like coiled-coil repeats (R). Using small angle neutron scattering (SANS) and the contrast variation technique, we specificallyprobed the structure of the three first consecutive repeats 1–3 (R1–3), a part of dystrophin known to physiologically interact withmembrane lipids. R1–3 free in solution was compared to its structure adopted in the presence of phospholipid-based bicelles.SANS data for the protein/lipid complexes were obtained with contrast-matched bicelles under various phospholipid composi-tions to probe the role of electrostatic interactions. When bound to anionic bicelles, large modifications of the protein three-dimensional structure were detected, as revealed by a significant increase of the protein gyration radius from 42 51 to60 54 A˚. R1–3/anionic bicelle complexes were further analyzed by coarse-grained molecular dynamics simulations. Fromthese studies, we report an all-atom model of R1–3 that highlights the opening of the R1 coiled-coil repeat when bound tothe membrane lipids. This model is totally in agreement with SANS and click chemistry/mass spectrometry data. We concludethat the sarcolemma membrane anchoring that occurs during the contraction/elongation process of muscles could be ensuredby this coiled-coil opening. Therefore, understanding these structural changes may help in the design of rationalized shorteneddystrophins for gene therapy. Finally, our strategy opens up new possibilities for structure determination of peripheral and inte-gral membrane proteins not compatible with different high-resolution structural methods.
LB  - PUB:(DE-HGF)16
C6  - pmid:30197181
UR  - <Go to ISI:>//WOS:000446056300010
DO  - DOI:10.1016/j.bpj.2018.07.039
UR  - https://juser.fz-juelich.de/record/856718
ER  -