Jin Hae Kim
University of Wisconsin, PhD
Proteins are intrinsically dynamic (Fig. 1). Many proteins, if not all, present multifaceted behaviors, significant portion of which cannot be explained without its structural plasticity. Nonetheless, protein structures were often studied at a specific state or condition, failing to reveal their potential structural versatility. In numerous cases, proteins accommodate structurally-distinctive conformations upon being exposed to different conditions or interacting with different molecules, and understanding to these structural transitions can be a key to elucidate the mechanistic details of the protein functions and activities. Notably, the native equilibrium states over diverse structural conformations of proteins are maintained with delicate balance, perturbation of which could shift the original structural equilibrium. Diseases of proteinaceous origins are often caused by this disruption of protein dynamics, and, among various factors, ‘protein aging’ is one of the major culprits that break the dynamic balance of protein structures. This is particularly true for many proteins showing amyloidogenic properties (such as the human tau protein; Fig. 1).
Amyloidogenic diseases, which are occurred by abnormal protein aggregation and amyloid formation, are one of the most old-aged, yet still-elusive challenges for us to appreciate and overcome. It is now believed that the aggregation-prone characters of proteins are rather intrinsic; the well-folded tertiary structures of proteins are necessary not only for their functionalities but also for prevention of their aggregation-prone states from being presented. Indeed, the amyloidogenic properties of proteins are often manifested by disruption of its native tertiary or quaternary structures, and again one of the major factors causing this structural disruption is the structural ‘aging’. To appreciate this, it is crucial to investigate dynamic structural features of the amyloidogenic proteins not only in its native ‘healthy’ states but also in the ‘aged’ states
Fig. 1 Structural flexibility of the human tau protein. This protein by itself does not have a specific structure, rather adopts multiple conformations (thus, called intrinsically disordered protein). This structural plasticity is closely correlated with its biological functions and pathological properties (Mukrasch, M. D. et al. PLoS Biol, 2009).
The long-term goal of our laboratory is to reveal the mechanism of the protein amyloidosis on the basis of complete characterization of the tertiary and quaternary structural features in static and dynamic states. In particular, we are interested in elucidating age-dependent structural transitions of proteins; determination of the ‘4-dimensional atomic-resolution structure’ of a protein would provide unprecedented insights regarding protein aging and aggregation mechanisms. In order to accomplish this goal, we target structural characterization of amyloidogenic proteins and chaperones, structural features of which are known to be affected by aging and to eventually cause various human diseases. The specific aims of our laboratory include the following:
1. Characterization of the dynamic structural features of proteins:
- Elucidation of the intrinsic dynamic features of proteins in order to appreciate their physiological functions as well as the pathological mechanisms
(a) Characterization of the dynamic features of amyloidogenic proteins to elucidate its amyloidosis mechanism
(b) Investigation of the structural plasticity of chaperones to understand their protection mechanisms against aggregation-prone proteins
Fig. 2. Although Fyn SH3 domain is a well-folded and non-amyloidogenic protein in its native state (orange), NMR spectroscopic study showed that this protein has an alternative low-populated amyloidogenic conformation (green) even in its non-amyloidogenic condition (Neudecker. et al. Science, 2012). This study indicates that once a certain stress (such as aging) perturbs the equilibrium of this protein, population of the amyloidogenic conformation increases, and the protein starts to aggregate. We believe that the case of Fyn SH3 domain represents the rather general pathogenic mechanism of protein amyloidosis.
Fig. 3. Structure of the ACD domain from αB-crystallin (left; Bakthisaran, R. et al. BBA, 2015), and the highly dynamic oligomeric states of αB-crystallin (right; Braun, N. et al. PNAS, 2011). Despite its physiological importance as an essential small heat-shock protein, structural plasticity of this protein is still elusive. Upon elucidating its dynamic features, we expect that the general working mechanisms of small heat-shock proteins are to be revealed.
2. Elucidation of the pathogenesis mechanisms of amyloidogenic proteins:
– Identification of the direct causes perturbing the native structural states of proteins
– Elucidation of the mechanisms facilitating aggregation/amyloid formation
– Structure determination of oligomers/aggregates/amyloids and characterization of their structural architecture.
Fig. 4. Proposed aggregation mechanisms of crystallins (Moreau, K. et al. Trends Mol Med, 2012). Aggregation of crystallins are the major cause of cataract. αB-crystallin, an isoform of crystallins, is essential heat shock protein that prevents aggregation of the other misfolded proteins, while the age-dependent modification of this protein is responsible for aggregation of various proteins including itself. We are interested in elucidating the age-dependent structural transitions of αB-crystallin, and in appreciating structural causes of its aggregation propensity.
3. Elucidation of the interactions between chaperones and pathogenic aggregation-prone proteins:
– Atomic-resolution characterization of the interaction mechanisms between chaperones and pathogenic substrate proteins
– Determination of diverse structural features of chaperones to interact with misfolded/aggregation-prone proteins
– Elucidation of the working mechanisms of chaperones and the resultant structural features of toxic substrate proteins
Fig. 5. The chaperoning activities of αB-crystallin involve various structural elements of this protein (Mainz, A. et al. NSMB, 2015). It is likely, therefore, that the structural plasticity of αB-crystallin correlates with its universal functionality as a chaperone. We expect that the structural elucidation of αB-crystallin in its interaction with various partners would provide clues to reveal the mechanisms how this protein acts as a universal chaperone in the human body.
- Javier Oroz*, Jin Hae Kim*, Bliss J. Chang, Markus Zweckstetter (2017) Nat. Struct. Mol. Biol. 24, 407-413 (*equal contribution).
- Jin Hae Kim, Javier Oroz, Markus Zweckstetter (2016) Angew. Chem. Int. Ed. 55, 16168-16171.
- Jin Hae Kim, Jameson R. Bothe, T. Reid Alderson, and John L. Markley (2015) Biochim. Biophys. Acta 1853, 1416-1428.
- Jin Hae Kim, T. Reid Alderson, Ronnie O. Frederick, and John L. Markley (2014) J. Am. Chem. Soc. 136, 11586–11589.
- Jin Hae Kim*, Jameson R. Bothe*, Ronnie O. Frederick, Johneisa C. Holder, and John L. Markley (2014) J. Am. Chem. Soc. 136, 7933-7942 (*equal contribution).
- Jin Hae Kim, Ronnie O. Frederick, Nichole M. Reinen, Andrew T. Troupis, and John L. Markley (2013) J. Am. Chem. Soc. 135, 8117-8120.
- Jin Hae Kim, Marco Tonelli, and John L. Markley (2012) Proc. Natl. Acad. Sci. U.S.A. 109, 454-459.