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Mechanical properties and function of CHMP2B in the ESCRT membrane remodelling and scission pathway

Abstract : The ESCRT-III protein complex mediates membrane remodeling in many cellular contexts. The ESCRT pathway has been extensively studied in vivo and partially reconstituted in vitro using yeast proteins. In Homo Sapiens, at least 12 ESCRT-III proteins exist, called Charged Multivesicular Body Protein (CHMP 1-7). Although, the main function of the ESCRT-III protein assemblies is to induce membrane scission by constricting membrane necks, the biophysical mechanism remains unclear and the mechanical properties of the CHMP polymers still poorly characterized. Moreover, the usually accepted sequence of recruitment of the major ESCRT components to the membrane prior to scission is CHMP4-CHMP3-CHMP2A but mammalian cells also have CHMP2B considered to be a CHMP2A isoform; so far, its role remains elusive. We have used biomimetic model systems and purified CHMP proteins to study in vitro protein affinity and effects on membrane by several techniques. We established that CHMP2B binding is enhanced with PI(4,5)P2 lipids, whereas the other human core components have no lipid specificity besides their negative charge. We showed that in the presence of CHMP2B, membranes become rigidified in contrast to CMHP2A as well as CHMP4 and CHMP3, suggesting that CHMP2A and CHMP2B have very distinctive properties. Finally, we show in disagreement with the proposed models, that CHMP4 alone cannot deform membranes. In fact, it requires the interaction with CHMP2B or CHMP2A+3 proteins to do so, forming polymer assemblies that stabilizes tubular membrane structures. These observations provide a novel basis for proposing possible mechanism for membrane constriction in the presence of the ATPase Vps4.
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Maryam Alqabandi. Mechanical properties and function of CHMP2B in the ESCRT membrane remodelling and scission pathway. Biophysics. Sorbonne Université, 2018. English. ⟨NNT : 2018SORUS525⟩. ⟨tel-02890310⟩

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