Conformational Dynamics of Presequence Protease (PreP) and interactions with specific substrates
Session Number
Project ID: PHYS 24
Advisor(s)
Nicky Bayhi; The University of Chicago
Dr. Wei Jen Tang; The University of Chicago
Discipline
Physical Science
Start Date
19-4-2023 10:20 AM
End Date
19-4-2023 10:35 AM
Abstract
Presequence protease (PreP) is encoded by the Pitrm1 gene which is an essential gene in mice and the defect in the Pitrm1 gene is linked to several human diseases. Presequence Protease (PreP) is a 117kDA M16C metalloprotease that cleaves presequence peptides and degrades amyloid ꞵ(Aꞵ). PreP has a C and N domain connected by a linker region together. There is a hollow catalytic core inside PreP, where the substrate enters and the proteolyzed products are released. A better understanding of the conformational dynamics of PreP that governs how PreP recognizes sequences and amyloid beta will guide the therapeutic innovation toward maintaining mitochondrial protein homeostasis (mito-proteostasis) and the mechanisms involved in cleaving. To investigate PreP, we applied all-atom molecular dynamics (MD) simulations to characterize the conformational heterogeneity of PreP. We observed a “hinge” and “grind” motion between the domains, characterizing the structural basis of the motion. Next, coarse-grained simulations were applied to show how known substrates induced a transition between the open and closed states of PreP that allows substrate capture and release. This research provides insight into the substrate-protein interactions of PreP and lays a foundation for future analysis of additional substrates in hopes to produce PreP variant with new functions.
Conformational Dynamics of Presequence Protease (PreP) and interactions with specific substrates
Presequence protease (PreP) is encoded by the Pitrm1 gene which is an essential gene in mice and the defect in the Pitrm1 gene is linked to several human diseases. Presequence Protease (PreP) is a 117kDA M16C metalloprotease that cleaves presequence peptides and degrades amyloid ꞵ(Aꞵ). PreP has a C and N domain connected by a linker region together. There is a hollow catalytic core inside PreP, where the substrate enters and the proteolyzed products are released. A better understanding of the conformational dynamics of PreP that governs how PreP recognizes sequences and amyloid beta will guide the therapeutic innovation toward maintaining mitochondrial protein homeostasis (mito-proteostasis) and the mechanisms involved in cleaving. To investigate PreP, we applied all-atom molecular dynamics (MD) simulations to characterize the conformational heterogeneity of PreP. We observed a “hinge” and “grind” motion between the domains, characterizing the structural basis of the motion. Next, coarse-grained simulations were applied to show how known substrates induced a transition between the open and closed states of PreP that allows substrate capture and release. This research provides insight into the substrate-protein interactions of PreP and lays a foundation for future analysis of additional substrates in hopes to produce PreP variant with new functions.