Premium
Pathologic Prion Protein Forms a Beta‐Solenoid Structure Initiated By Misfolding of Its Flexible N‐terminal Region
Author(s) -
Replogle Jessica,
Calderon Irene,
McDowell Daniel,
Stanisic Sophia,
Welling Ann,
Suder Karen
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04046
Subject(s) - prion protein , solenoid , terminal (telecommunication) , beta (programming language) , chemistry , microbiology and biotechnology , biology , physics , computer science , medicine , pathology , disease , telecommunications , quantum mechanics , programming language
Prion diseases, such as Creutzfeld‐Jakob disease, Gerstman‐Sträussle‐Scheinker syndrome, fatal familial insomnia, and kuru, are neurodegenerative diseases characterized by neuronal loss, the proliferation of glial cells, absence of an inflammatory response, and a spongiform appearance of neural elements. They occur due to an abnormal accumulation of an isoform of a host cell protein, the prion protein (PrP) found in neuronal and non‐neuronal cells. In this process, PrP that is membrane‐bound, designated as PrPC, is converted to a pathologic form, PrPSc. This conversion results from a conformational change in PrPC rather than a chemical modification. The Summit Country Day School MSOE Center for BioMolecular Modeling MAPS Team used 3D modeling and printing technology to examine structure‐function relationships of the PrP and its pathogenic form, PrPSc. PrPC exists primarily in an alpha‐helical conformation with a flexible N‐terminal region and a C‐terminal globular domain. The C‐terminus consists of two β‐sheets, three α‐helices, and two potential sites for N‐linked glycosylation. The N‐terminus of PrPC is composed of approximately 125 amino acids, with octarepeat regions. In contrast, PrPSc forms highly complex structures characterized by a beta‐solenoid, a protein‐fold composed of repeating beta‐subunits. The insoluble beta‐solenoid structure of PrPSc forms amyloid fibrils, is prone to aggregation, and is thought to be both pathogenic and infective. The end of the PrPSc aggregate can form hydrogen bonds with additional PrP molecules, elongating the pathogenic PrPSc structure. Murine experiments point to a model of antibody‐binding to the globular C‐terminal domain of PrPC, which causes the PrPC flexible N‐terminal region to misfold and transmit a pathogenic signal to neurons. The murine model mimics the interaction of PrPSc with PrPC. This project demonstrates the difference in structure between PrPC and PrPSc and highlights possible mechanisms for its neurotoxicity and propagation. Understanding the structure of PrP will elucidate potential targets in preventing pathology and infectivity in prion diseases.