Protein Research
Laboratory

Proteins must acquire and maintain their proper three-dimensional structures to perform their cellular functions. However, environmental and physiological stresses can destabilize proteins, leading to misfolding, aggregation, and loss of function. Cells therefore employ diverse protein quality-control systems to maintain protein homeostasis (proteostasis). Molecular chaperones assist protein folding and prevent irreversible aggregation, while proteases recognize and eliminate damaged, misfolded, or unnecessary proteins.

Our laboratory investigates the structural and molecular mechanisms underlying these protein quality-control processes. Our research encompasses ATP-dependent folding and degradation machineries as well as ATP-independent molecular chaperones that protect proteins from stress-induced misfolding and aggregation.

Chaperonins (CPNs) are ATP-dependent molecular chaperones that provide an enclosed environment for productive protein folding. By transiently encapsulating non-native polypeptides within a central cavity, chaperonins prevent inappropriate intermolecular interactions and promote correct folding. Our laboratory has investigated the structural organization and ATP-dependent conformational changes of chaperonin systems to understand how nucleotide-driven structural transitions regulate substrate encapsulation and folding. These studies provide insight into how ATP-powered molecular machines actively maintain protein folding homeostasis.

AchC (acid-activated hand-like chaperone), a bacterial molecular chaperone, protects proteins from acid-induced damage. In Pseudomonas aeruginosa, AchC undergoes pH-dependent conformational rearrangements and changes in oligomeric state, leading to exposure of regions involved in client recognition and activation of its chaperone function. Activated AchC prevents the aggregation of acid-denatured proteins and promotes their subsequent recovery without requiring ATP. These findings reveal a pH-responsive mechanism that directly couples environmental acidification to molecular chaperone activation, enabling bacterial cells to maintain proteome integrity under acidic stress.

DJ-1 (Parkinson disease protein 7; PARK7) is a multifunctional protein implicated in diverse cellular processes and human diseases, including Parkinson’s disease. Human DJ-1 possesses several biochemical activities, including molecular chaperone activity. Our research team first demonstrated the chaperone activity of human DJ-1 based on its structural similarity to the Escherichia coli chaperone Hsp31. We also discovered that inorganic phosphate induces filamentous aggregation of DJ-1 and determined the high-resolution crystal structure of these aggregates. These studies have provided insights into the relationship between the structural state, chaperone activity, and aggregation behavior of DJ-1.

Lon protease is an ATP-dependent protease of the AAA+ (ATPases associated with various cellular activities) family and plays an important role in protein quality control by eliminating abnormal, damaged, and short-lived regulatory proteins. Lon proteases are widely distributed across all kingdoms of life and couple ATP hydrolysis to substrate recognition, unfolding, translocation, and proteolytic degradation. Our laboratory determined the crystal structure of Lon protease, revealing the molecular architecture of its sequestered proteolytic chamber, and has investigated how its ATPase and protease modules are structurally organized to control substrate degradation. These studies provide a structural basis for understanding how ATP-driven proteolytic machines remove damaged proteins and preserve proteome integrity.

Together, our studies address complementary stages of protein quality control—from productive protein folding, to protection against stress-induced misfolding and aggregation, and finally to the ATP-dependent removal of damaged proteins. Through structural biology, biochemical analysis, and biophysical approaches, we aim to understand how protein quality-control factors recognize non-native proteins, undergo functional conformational transitions, and preserve proteostasis under diverse cellular and environmental stresses.

[Related publications]

Soojeong Ham^¶, Yeon-Ju Jung^¶, Hyunhee Kim, Sun-Shin Cha*, Changhan Lee*
 "pH-Driven Two-Stage Conformational Switching Activates an Acid-Responsive Chaperone"

 Angewandte Chemie International Edition, Oct 04 Accepted. (2026)

Namjoon Cho^¶, Jaegeon Joo^¶, Sunkyung Choi, Bu-Gyeong Kang, Andrew J.Lee, So-Yeon Youn, Su-Hyung Park, Eun-Mi Kim, Eliezer Masliah, Yuji Ko, Sun-Shin Cha*, Inkyung Jung*, Kee K.Kim*

"A novel splicing variant of DJ-1 in Parkinson's disease induces mitochondrial dysfunction"

Heliyon,  Feb 26;9(3):e14039 (2023)

Sanguk Yun*, Sun-Shin Cha and Jae Ho Kim*

"DJ-1 promotes cell migration by interacting with Mena, the mammalian homolog of Drosophila enabled"

 Advances in Biological Regulation, May:88:100943 (2023)

Julee Kim, Sangki Baek, Yean Ju Hong, Michelle Novais de Paula, Musharrat Jahan Prima, Yeon-Mok Oh, Sun-Shin Cha, Jeong Tae Do, Yeon Jin Jang, Han Choe*

"DJ-1 can replace FGF-2 in defined media and feeder-free condition for long-term culture of human pluripotent stem cells"

International Journal of Molecular Sciences, May 31;22(11):5954 (2021)

Min Soo Kim^¶,Sangmin Lee^¶,Sanguk Yun, Pann-Ghill Suh, Jongmi Park, Minghua Cui, Sun Choi, Sun-Shin Cha*, Wook Jin*

"Inhibitory effect of tartrate against phosphate-induced DJ-1 aggregation"

International Journal of Biological Macromolecules,Feb; 107(Pt B): 1650-1658 (2018)

Mi-Kyung Lee^¶, Min-Sung Lee^¶,Da-Woon Bae, Dong-Hwa Lee, Sun-Shin Cha*, Seung-Wook Chi*

"Structural characterization of interaction between DJ-1 and Bcl-X_L using NMR spectroscopy"

Biochemical and Biophysical Research Communications, Jan 1; 495(1):1067-1073 (2018)

Young Jun An^¶, Sara E. Rowland^¶, Jung-Hyun Na^¶, Dario Spigolon, Seung Kon Hong, Yeo Joon Yoon, Jung-Hyun Lee, Frank T. Robb*, and Sun-Shin Cha*

"Structural and mechanistic characterization of a novel archaeal-like chaperonin from a thermophilic bacterium"

Nature Communications, Oct 10;8(1):827 (2017)

Young Jun An, Sara E. Rowland, Frank T. Robb, Sun-Shin Cha*

"Purification, crystallization, and preliminary X-ray crystallographic analysis of the Group III chaperonin from Carboxydothermus hydrogenoformans"

Journal of Microbiology, Jun;54(6):440-444 (2016)

Young Jun An, Jung-Hyun Na, Myung-Il Kim, and Sun-Shin Cha*

"Structural basis for the ATP-independent proteolytic activity of LonB proteases and reclassification of their AAA+ modules"

Journal of Microbiology, Oct;53(10):711-717 (2015)

Hai-Tuong Le, Valérie Gautier, Fatoum Kthiri,, Abderrahim Malki, Nadia Messaoudi, Mouadh Mihoub, Ahmed Landoulsi, Young Jun An, Sun-Shin Cha and Gilbert Richarme*

"YajL, the prokaryotic homolog of the Parkinsonism associated protein DJ-1, functions as a covalent chaperone for the thiol proteome"

Journal of Biological Chemistry Feb 17;287(8):5861-5870(2012)

Hoi Jong Jung, Sangok Kim, Yun Jae Kim, Min-Kyu Kim, Sung Gyun Kang, Jung-Hyun Lee, Wankyu Kim*, and Sun-Shin Cha*

"Dissection of the dimerization modes in the DJ-1 superfamily"

Molecules and Cells Feb;33(2):163-171(2012)

Jung-Min Kim, Hong-In Shin, Sun-Shin Cha, Chang Sup Lee, Bok Sil Hong, Seyoung Lim, Hyun-Jun Jang, Jaeyoon Kim, Yong Ryoul Yang, Yun-Hee Kim, Sanguk Yun, Girdhari Rijal, Whaseon Lee-Kwon, Jeong Kon Seo, Yong Song Gho, Sung Ho Ryu, Eun-Mi Hur, and Pann-Ghill Suh*

"DJ-1 promotes angiogenesis and osteogenesis by activating FGF receptor-1 signaling"

Nature CommunicationsDec 18;3:1296 (2012)

Sun-Shin Cha^¶*, Young Jun An^¶, Chang Ro Lee, Hyun Sook Lee, Yeon-Gil Kim, Sang Jin Kim, Kae Kyoung Kwon, Jung-Hyun Lee, Michael R. Maurizi*, Sung Gyun Kang*

"Crystal structure of Lon protease: Molecular architecture of gated entry to a sequestered degradation chamber"

The EMBO Journal Oct 20; 29(20):3520-3530 (2010)

Young Jun An, Chang-Ro Lee, Supangat Supangat, Hyun Sook Lee, Jung-Hyun Lee, Sung Gyun Kang, and Sun-Shin Cha*

"Crystallization and preliminary x-ray crystallographic analysis of Lon from Thermococcus onnurineus NA1"

Acta Crystallogr Sect F Struct Biol Cryst Commun Jan 1;66(Pt 1):54-56 (2010)

Sun-Shin Cha*, Ha Il Jung, Hyesung Jeon, Young Jun An, In-Kwon Kim, Sanguk Yun, Hyun Jin Ahn, Kwang Chul Chung, Sang Hee Lee, Pann-Ghill Suh, and Sa-Ouk Kang*

"Crystal structure of filamentous aggregates of human DJ-1 formed in an inorganic phosphate-dependent manner"

Journal of Biological Chemistry Dec 5;283(49):34069-34075 (2008)

Sun-Joo Lee, So Jung Kim, In-Kwon Kim, Junsang Ko, Chang-Sook Jeong, Gyung-Hwa Kim, Chankyu Park, Sa-Ouk Kang, Pann-Ghill Suh, Heung-Soo Lee, and Sun-Shin Cha*

"Crystal structures of human DJ-1 and Escherichia coli Hsp31 that share an evolutionarily conserved domain"

Journal of Biological ChemistryNov 7, 278, 44552-44559 (2003)