Procollagen Assembly

Massachusetts Institute Of Technology, Cambridge MA

Investigators

Abstract

This project seeks to uncover how collagen, the molecular scaffold for animal life, assembles inside cells into the complex three-dimensional structures required to form skin, bone, cartilage, and other tissues. The advances in fundamental knowledge of collagen biochemistry achieved will have translatable impact, yielding an enhanced ability to create designer biomaterials and an improved understanding of collagen misfolding-related genetic disorders. The research is tightly integrated with continuation and expansion of a successful science outreach program targeting the homeschool community. One arm of the program involves MIT HIP-SAT (Homeschool Internship Program in Science and Technology), a nationally competitive program that brings homeschooled students to leading labs at MIT for funded summer research internships. A second arm of the program targets children in the 8–14 age range, distributing hands-on molecular biology modeling kits that capture students’ attention with chemical concepts that underpin life processes and training the community in effective use of these kits. The fibrillar procollagens are composed of a lengthy, uninterrupted triple-helical domain flanked by a small N-propeptide and somewhat larger globular C-propeptide (C-Pro). The triple helix itself, which is the fundamental structural element of mature collagen, is a trimeric structure in which three distinct, left-handed helical strands wrap around each other to form the right-handed, parallel triple helix. In fibrillar collagens, the most abundant types, these triple helices can span up to ~1000 amino acids in length. These lengthy, repetitive triple-helical domains cannot fold properly on their own. Instead, they require assistance to ensure proper strand selection (some collagens are homotrimeric, while others form 2:1 or even 1:1:1 heterotrimers) and alignment of individual polypeptides. Remarkably, the molecular basis for collagen homo- versus hetero-trimerization is not yet known. This research integrates strategies from synthetic chemistry, biochemistry, structural biology, and cell biology to fill this key knowledge gap. The outcomes will be a new paradigm for understanding collagen assembly mechanisms, as well as a molecular explanation of the complex interplay between thermodynamic and kinetic effects that ensures proper collagen assembly. These results will impact fundamental understanding of the most abundant protein in humans, enable biomaterial applications, and elucidate disease-relevant biology. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.