VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites

Abstract

SUMMARYMembrane contact sites (MCSs) between organelles are heterogeneous in shape, composition and dynamics. Despite this diversity, VAP proteins act as receptors for multiple FFAT motif-containing proteins and drive the formation of most MCSs involving the endoplasmic reticulum (ER). Although the VAP‒FFAT interaction is well characterized, no model explains how VAP adapts to its partners in various MCSs. We report here that VAP-A localization to different MCSs depends on its intrinsically disordered regions (IDRs). We show that VAP-A interaction with PTPIP51 and VPS13A at ER‒mitochondria MCS conditions mitochondria fusion by promoting lipid transfer and cardiolipin buildup. VAP-A also enables lipid exchange at ER‒Golgi MCS by interacting with OSBP and CERT. However, removing IDRs from VAP-A restricts its distribution and function to ER‒ mitochondria MCS, at the expense of ER‒Golgi MCS. Our data suggest that IDRs of VAP-A do not modulate its preference towards specific partners, but adjust its geometry to the constraints linked to different MCS organization and lifetime. Thus, VAP-A conformational flexibility mediated by its IDRs ensures membrane tethering plasticity and efficiency.

Controlling contacts—Molecular mechanisms to regulate organelle membrane tethering

“…[ 94 ] VAPA also contains intrinsically disordered regions, which enable versatile tethering at MCS and contribute to membrane tethering plasticity and efficiency. [ 95 ]…”

“…[94] VAPA also contains intrinsically disordered regions, which enable versatile tethering at MCS and contribute to membrane tethering plasticity and efficiency. [95] Several tether proteins contain a coiled-coil domain (e.g., VAP, ACBD4, ACBD5, PTPIP51, OSBP, MIGA2), which can mediate di-/oligomerization of the proteins (Figures 1C and 2F). ER-resident VAPA and VAPB, for example, form homo-and heterodimers.…”