Cells are surrounded and contained by a plasma membrane consisting of a double layerof fats and proteins. These proteins monitor and facilitate the movement of food, oxygen and
messages in and out of the cell, and help neighboring cells communicate. Membrane proteins are
manufactured in a cell compartment called the endoplasmic reticulum. Cellular machines called
ribosomes manufacture proteins that need to be secreted or embedded into the cell’s membranes.
As these proteins are made, they are pulled into the endoplasmic reticulum so they can be
stabilized, folded correctly and inserted in the membrane. A cellular machine in this
compartment’s membrane that aids this process is the endoplasmic reticulum membrane protein
complex (EMC). The EMC is a large protein complex made up of ten subunits in mammalian cells.
EMC’s intricate structure and large range of clients it stabilizes underscore its importance in
maintaining protein homeostasis. Our studies illuminate the structural and mechanistic basis of
EMC’s multifunctionality and point to its role in differentially regulating the biogenesis of distinct
client protein classes. Beyond the molecular role of EMC, we build a genetic roadmap of the EMC
in mammalian cells and helping decipher its crucial role in maintaining cholesterol homeostasis.
Together, this work lays the framework for understanding both the molecular and physiological
role of the EMC in mammalian cells.