<p>Allosteric Regulation of the Human Proteasome</p> Gauss Centre for Supercomputing e.V.

LIFE SCIENCES

Allosteric Regulation of the Human Proteasome

Principal Investigator:
Michal H. Kolář

Affiliation:
Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry

Local Project ID:
GCS-prot

HPC Platform used:
Hazel Hen of HLRS

Date published:

The proteasome is a stochastic 2.5 MDa nanomachine responsible for protein degradation in eukaryotic cells via the ubiquitin-proteasome pathway [1]. It helps maintaining the delicate balance of protein concentrations, thus plays a fundamental role in cell life cycle. Modulation of proteasome function has a direct effect on cell homeostasis, disruption of which often leads to the cell death [2].

The proteasome contains two major functional parts: a 20S core particle (CP) and a 19S regulatory particle (RP) depicted in Figure 1. The CP is a barrel-shape complex of several protein subunits organized in four rings - two α-rings and two β-rings in a stacked αββα arrangement. Three β-subunits (β1, β2, and β5) have been shown to catalyze the proteolysis. The α-ring creates a gate (pore) through which an unfolded protein enters the lumen of CP, where it is proteolysed.

Understanding the proteasome structure and function poses a fundamental scientific challenge. However, the proteasome is under intensive investigation also due to a tremendous potential for medicinal applications. Most notably, several ligands have been discovered to inhibit the CP. Oprozomib (OPR) [3] is one of those which have already reached the market as potent anti-cancer agents.

To characterize the effect of OPR on the proteasome dynamics, and possibly to describe the proposed allosteric pathway [4], the authors performed all-atom molecular dynamics (MD) simulations of several proteasome constructs with and without OPR. They collected roughly 100 microseconds of trajectories of systems with 0.8–1.6 million particles. Since the full atomistic interactions are necessary to faithfully describe the anticipated allostery, the simulations of such an extended biomolecular system could only be carried out at Tier0/1 HPC resources, in this case on HPC system Hazel Hen at the High-Performance Computing Center Stuttgart.

Most of the subunits are sufficiently converged (Fig. 2A). The largest structural differences between the native and inhibited proteasome were found for surface loops and terminal chains and are likely related to the limited simulation length. The catalytic subunit β5 contains loops, which seem to be structurally sensitive to the presence of the inhibitor more than other β5 parts: one at the interface with α4, and another at the interface with β3 (Fig. 2B). The inhibitor extends from β5 catalytic cavity to the proteasome lumen and interacts with α2 (not shown).

The authors analyzed how atomic fluctuations, which are a natural outcome of the MD simulations, change upon inhibition. The changes span the entire proteasome and suggest possible pathways transferring the signal from the β5 subunits towards the RP (Fig. 2C). The fluctuations are currently analyzed in more detail. The results shed a light onto proteasome dynamics and will help us understand the regulation of the protein degradation.

Project contributors

Dr. Lars V. Bock1, Prof. Helmut Grubmüller1

1Department of theoretical and computational biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen (Germany)

References

[1] Saeki, Y., and Tanaka, K. (2012). Assembly and Function of the Proteasome. In Ubiquitin Family Modifiers and the Proteasome, R.J. Dohmen, and M. Scheffner, eds. (Humana Press), 315.

[2] Rechsteiner, M., & Hill, C. P. (2005). Trends Cell Biol.15, 27.

[3] Demo, S.D., Kirk, C.J., Aujay, M.A., et al. (2007). Cancer Res 67, 6383.

[4] Haselbach, D., Schrader, J., Lambrecht, F., et al. (2017). Nat. Commun. 8, ncomms15578.

Scientific Contact

Dr. Michal H. Kolář
Department of Theoretical and Computational Biophysics
Max Planck Institute for Biophysical Chemistry
A Fassberg 11, D-37077 Göttingen (Germany)
e-mail: michal.kolar [@] mpibpc.mpg.de

https://www.mpibpc.mpg.de/grubmueller

Local project ID: GCS-prot

April 2020

Tags: HLRS MPI Göttingen Life Science