Folding and Quality Control Mechanisms of Procollagen

Abstract

Procollagens undergo a complex folding process with the assistance of various ER proteostasis network components and enzymes that introduce post-translational modifications. In Chapter 2, we investigate the biological role of one of the post-translational modifications, the highly conserved N-glycosylation on procollagen C-propeptides by generating and characterizing multiple mouse models that lack the N-glycan on procollagen-I. We show that the lack of N-glycan can affect procollagen folding inside the cells, which translates to reduced bone mass in mice lacking the N-glycan. These data provide new insights into the roles of the evolutionarily conserved, yet underappreciated collagen’s N-glycan. Mutations in procollagen genes and other proteins important for procollagen folding often cause misfolding defects in procollagen that can ultimately lead to disease. In Chapter 3, we explore the various molecular mechanisms that the ER proteostasis network can use to recognize diverse classes of misfolding procollagen variants. Specifically, we apply cell engineering and quantitative mass spectrometry to elucidate the interactomes of diverse osteogenesis imperfecta-causing procollagen α1(I) variants with distinct folding defects, and show that ER proteins differentially engage with these misfolding procollagen variants. These findings provide a foundation for illuminating quality control pathways that the different types of misfolding procollagen variants are subject to during their biogenesis. Taken together, the work in this thesis meaningfully advances our knowledge in the mechanisms of procollagen folding and quality control.