title: Essential function of the N-termini tails of the proteasome for the gating mechanism revealed by molecular dynamics simulations.
abstract: Proteasome is involved in the degradation of proteins. Proteasome activators bind to the proteasome core particle (CP) and facilitate opening a gate of the CP, where Tyr8 and Asp9 in the N-termini tails of the CP form the ordered open gate. In a double mutant (Tyr8Gly/Asp9Gly), the N-termini tails are disordered and the stabilized open-gate conformation cannot be formed. To understand the gating mechanism of the CP for the translocation of the substrate, four different molecular dynamics simulations were carried out: ordered- and Tyr8Gly/Asp9Gly disordered-gate models of the CP complexed with an ATP-independent PA26 and ordered- and disordered-gate models of the CP complexed with an ATP-dependent PAN-like activator. The free-energies of the translocation of a polypeptide substrate moving through the gate were estimated. In the ordered-gate models, the substrate in the activator was more stable than that in the CP. The conformational entropy of the N-termini tails of the CP was larger when the substrate was in the activator than in the CP. In the disordered-gate models, the substrate in the activator was more destabilized than in the ordered-gate models. The mutated N-termini tails became randomized and their increased conformational entropy could no longer increase further even when the substrate was in the activator, meaning the randomized N-termini tails had lost the ability to stabilize the substrate in the activator. Thus, it was concluded that the dynamics of the N-termini tails entropically play a key role in the translocation of the substrate.
authors.affiliation: Quantum Beam Science Directorate and Center for Computational Science and e-Systems, Japan Atomic Energy Agency, Kyoto, 619-0215, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ishida
mesh_terms: D001105:Archaea / Q000201:enzymology; D019843:Archaeal Proteins / Q000737:chemistry* / Q000378:metabolism*; D019295:Computational Biology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D021381:Protein Transport; D059748:Proteolysis
chemical_list: D019843:Archaeal Proteins; D046988:Proteasome Endopeptidase Complex
keywords: PA26; PAN-like; adaptively biased molecular dynamics (ABMD); free energy of translocation; hybrid proteasome; proteasome core particle (CP)