Phone: (303) 492-5707
Ph.D. Mayo Clinic College of Medicine, 2005
Postdoctoral fellow, Harvard Medical School, 2005-2012
Proteasome Biogenesis: Mechanisms of Building a Unique Molecular Machine via its Assembly Chaperone System
Life uses molecular machines. For essential living processes, cells build these machines from individual protein subunits by arranging them into small parts, and then into functional complexes. Through understanding assembly mechanisms, we can gain critical insights into how cells create and dynamically adjust functions of these machines in constantly changing physiological environments. For this, our lab focuses on a unique molecular machine, the proteasome, a central protease complex in eukaryotes, consisting of at least 33 subunits. Rapid and selective proteolysis by the proteasome is critical for all aspects of the cell biology and many pathogenic conditions including neurodegenerative diseases and cancers. The proteasome is essential to life. How do cells assemble this proteolytic machine, so that it can perform robustly and precisely for disparate cellular processes?
To address this question, my research program investigates molecular mechanisms and functions of an assembly chaperone system for the proteasome (Park et al, Nature 2009; Roelofs and Park et al, Nature 2009). The system contains 4 phylogenetically distinct proteins with one of them being a known oncoprotein, Gankyrin. These chaperones promote the assembly of the hexameric ATPase ring of the proteasome through uniquely shared mode of action; each chaperone binds the C-terminal domain of the specific ATPase subunit. My most recent work has shown that chaperone actions are intimately coupled with the ATPase ring function (Park et al., Nature 2013). The chaperone system raises an important question: how do assembly chaperones regulate and contribute to proteasome functions without being a component of the fully-formed and functional machine? To address this question, we will elucidate (i) molecular mechanisms and functions of individual chaperones, (ii) regulatory pathways orchestrating active assembly and disassembly of the proteasome, (iii) functional connection between proteasome biogenesis and genome maintenance, using combined approaches of biochemistry, cell biology and genetics in budding yeast as well as mammalian cell line system.
Park S*, Li X*, Kim HM*, Singh RC, Tian G, Hoyt MA, Lovell S, Battaile KP, Zolkiewski M, Coffino P, Roelofs P, Cheng Y, and Finley D.
Reconfiguration of the proteasome during chaperone-mediated assembly.
Nature 7450, 512-6 (2013). *Equal contributions
Ehlinger A, Park S, Fahmy A, Lary J, Cole J, Finley D and Walters KJ.
Conformational Dynamics of the Proteasome ATPase Rpt6 and its Interaction with Rpn14.
Structure 5, 753-65 (2013).
Tian G, Park S, Lee MJ, Huck B, McAllister F, Hill CP, Gygi SP, Finley D.
An asymmetric interface between the regulatory particle and core particle of the proteasome.
Nature Structural & Molecular Biology 18, 1259-67 (2011).
Park S, Kim W, Tian G, Gygi SP, Finley D.
Structural defects in the regulatory particle-core particle interface of the proteasome induce a novel proteasome stress response.
Journal of Biological Chemistry 286, 36652-66 (2011).
*Lee BH, *Lee MJ, Park S, Oh DC, Elsasser S, Chen PC, Gartner C, Dimova N, Hanna J, Gygi SP, Wilson SM, King RW, Finley D.
Enhancement of proteasome activity by a small-molecule inhibitor of USP14.
Nature 467, 179-184 (2010). *Equal contributions
Research Highlights. Protein degradation: Time for trimming.
Nature Reviews Molecular Cell Biology 11, 754-5 (2010).
Park S, Roelofs J, Kim W, Robert J, Schmidt M, Gygi SP, Finley D.
Hexameric assembly of the proteasomal ATPases is templated through their C termini.
Nature 459, 866-870 (2009).
Roelofs J, Park S, Haas W, Tian G, McAllister FE, Huo Y, Lee BH, Zhang F, Shi Y, Gygi SP, Finley, D.
Chaperone-mediated pathway of proteasome regulatory particle assembly.
Nature 459, 861-865 (2009).
- News and Views. The proteasome assembly line. Nature 459, 787-788 (2009).
- Research Highlights. Protein degradation: Assembly from the base.
Nature Reviews Molecular Cell Biology 10, 442-443 (2009).
*Kleijnen MF, *Roelofs J, Park S, Hathaway NA, Glickman M, King RW, Finley D.
Stability of the proteasome can be regulated allosterically through engagement of its proteolytic active sites.
Nature Structural & Molecular Biology 14, 1180-1188 (2007). *Equal contributions
Research Roundup. A chewing proteasome is stabilized. Journal of Cell Biology 179, 1086 (2007).
Smith DM, Chang SC, Park S, Finley D, Cheng Y, Goldberg AL.
Docking of the proteasomal ATPases' carboxyl termini in the 20S proteasome's alpha ring opens the gate for substrate entry.
Molecular Cell 27, 731-744 (2007).
Preview. Unlocking the proteasome door. Molecular Cell 27, 865-867 (2007).
Park S, James CD.
ECop (EGFR-coamplified and overexpressed protein), a novel protein, regulates NF-kappaB transcriptional activity and associated apoptotic response in an IkappaBalpha-dependent manner.
Oncogene 24, 2495-2502 (2005).
Park S, James CD.
Lanthionine synthetase components C-like 2 increases cellular sensitivity to adriamycin by decreasing the expression of P-glycoprotein through a transcription-mediated mechanism.
Cancer Research 63, 723-727 (2003).