Mechanisms of selective protein secretion: towards therapeutic interventions.

Protein secretion is an essential process that delivers a diverse array of proteins to the extracellular milieu. We study the conserved cellular machinery that mediates the first step of protein secretion, export from the endoplasmic reticulum. We aim to understand how cells maintain selectivity when handling a vast diversity of protein sequence and structure. Here, we aim to dissect the molecular mechanisms by which cargo proteins are selectively captured into nascent vesicles. We then aim to leverage redundancy in this step to specifically abrogate a subset of interactions using small molecules, thereby inhibiting secretion of a subset of proteins. Our aims encompass a blend of mechanistic studies that dissect protein-protein interactions for two export receptors, chosen for their conservation and medical relevance (Aims 1 and 2), complemented by cell-based approaches to reveal the spectrum of proteins that engage these machineries in diverse cell types (Aim 3), and small molecule screens for modulators of these interactions (Aim 4). At the completion of our studies, I anticipate having a molecular understanding of how key medically important cargoes engage their receptors, how such interactions drive unique secretion signatures in diverse cells, and a set of tool compounds that perturb interactions to impact secretion.