The Synaptotagmin-1 C2B domain is a key regulator in the stabilization of the fusion pore

CAPAROTTA MARCELO; TOMES CN; MAYORGA L; MASONE D

JOURNAL OF CHEMICAL THEORY AND COMPUTATION

AMER CHEMICAL SOC

Lugar: Washington; Año: 2020 vol. 16 p. 7840 - 7851

1549-9618

Fusion pores serve as an effective mechanism to connect intracellular organelles andto release vesicle contents during exocytosis. A complex lipid rearrangement takes placeas membranes approximate, bend, fuse and establish a traversing water channel to definethe fusion pore, linking initially isolated chambers. Thermodynamically, the process isunfavorable and thought to be mediated by specialized proteins. In this work, we haveused enhanced molecular dynamics to induce fusion pores from initially flat and parallellipid bilayers and to describe the role of Synaptotagmin-1 C2B during the process.We have obtained free energy profiles of the whole lipid reorganization in biologicallyrealistic membranes, going from planar and parallel bilayers, through stalk hemifusionto water channel formation. Our results point to Synaptotagmin-1 C2B polybasicregion KRLKKKKTTIKK (positions 321-332) as the key to lipid reorganization control,inducing the formation of phosphatidylinositol bisphosphate clusters to stabilize thefusion pore.