Procollagen Folding in Health and Disease

Procollagen is a large, complex, and in many ways, unusual protein that is ubiquitous in the human body and in all animals. Decades of research have advanced our understanding of how cells fold and secrete this protein, nonetheless, many questions remain concerning procollagen biosynthesis, and how the process can go awry in the case of collagenopathies. Understanding how these mechanisms break down in disease is key to (1) gaining a better fundamental understanding of how these mechanisms function, and (2) developing effective and targeted strategies for disease modifying treatment. In this thesis, we discuss some of the newly appreciated mechanisms involved in procollagen folding in health and disease. In Chapter 2, we explore the molecular basis of procollagen assembly, and uncover a new role for the triple helical domain sequence in guiding trimer assembly. In Chapters 3 and 4, we develop, characterize, and deploy an expandable human cartilage model to examine the processes of procollagen proteostasis that break down in the cases of the chondrodysplasia-inducing Gly1170Ser and Arg719Cys substitutions in procollagen-II, respectively. In Appendix C, we explore the functional differences between two alternatively spliced forms of the procollagen-II N-propeptide and speculate about the role and importance of aspartate hydroxylation in ocular function and homeostasis. Collectively, the work described in this thesis advances our understanding of the molecular mechanisms involved in procollagen proteostasis in health and disease.

Name thesis:degree_name

Doctoral

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Chemistry

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2024

Author dc:creator

• Yammine, Kathryn Marie

Advisor dc:contributor.advisor

• Shoulders, Matthew D.

Statement dc:rights

• In Copyright - Educational Use Permitted
• Copyright retained by author(s)

Licence dc:rights.uri

• https://rightsstatements.org/page/InC-EDU/1.0/

Handle dc:identifier.uri

https://hdl.handle.net/1721.1/157067

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/157067