Allison Myers
Research Mentor(s): Nils Walter
Mentor Department: Chemistry
Authors: Allison Myers, Laxmikanta Khamari, Nils Walter
Session: Session 4 (1:00pm – 1:50pm)
Presentation Type: Poster 13
Abstract
The regulatory dysfunction of certain mutations of Valosin-Containing Protein (VCP) complex (including cofactors Ufd-1 and Npl-4) and its role in unfolding misfolded polyubiquitinated substrates for further degradation by the proteasome is associated with many neurodegenerative diseases such as Frontotemporal Dementia (FTD) and ALS, although the specific mechanisms of these diseases are not well understood. To accelerate the understanding of the role mutations of the hexameric VCP complex play in the unfolding mechanism, we conducted a study of the binding kinetics between VCP mutants, the Npl-4 cofactor, and polyubiquitinated substrates. Our single molecule fluorescence approach compared the binding kinetics of wild–type and pathological Npl-4 cofactor to wild–type and pathological mutant VCP complexes. The results show a change in cofactor binding affinity to the mutated version of the VCP complex. These findings indicate that the mutation in the VCP complex contributes to a decreased binding affinity of substrate to the unfoldase, and the decreased association of ubiquitinated substrates to the complex could be a cause of the neurodegenerative diseases that accumulate dysfunctional proteins in the body. The altered binding affinity for mutated VCP complex and Npl-4 cofactor provides a basis for the mechanism of these diseases and their progression, and a target for future novel drug discovery to treat said diseases.
