A hallmark of eukaryotic cells is the compartmentalization of cellular functions within membrane-enclosed organelles. Small (50-100 nm diameter) vesicles traffic between organelles transporting select cargo protein and lipid molecules. Selective transport ensures the maintenance of the organelle composition and is the underlying mechanism of key cellular processes such as endocytosis, secretory function, and exocytosis of hormones and neurotransmitters. The COPII coat complex mediates the first step in secretory traffic by incorporating newly synthesized proteins into vesicles that bud from the endoplasmic reticulum (ER) and fuse with early Golgi compartments. The current proposal seeks to study the molecular determinants of cargo selection by the mammalian COPII complex using a combination of biochemical and X-ray crystallographic methods. Specifically, the proposal aims to study biologically important mammalian cargo molecules including: secreted growth factors, SNAREs, cell surface receptors, and membrane channels. The ultimate aim is to provide a molecular level description of all mammalian ER export motifs and their interaction with the COPII coat complex.