Proteostasis of membrane proteins in health and disease
My laboratory aims to understand protein homeostasis (proteostasis) of membrane proteins in health and disease. Membrane proteins are major drug targets; loss of their proteostasis and thus function leads to numerous diseases, including neurodegerative diseases and cardiovascular diseases. To function, membrane proteins need to fold into their native structures in the endoplasmic reticulum (ER) for trafficking to the plasma membrane in a fully functional state. Mutations in a given protein could lead to protein misfolding and excessive ER-associated degradation (ERAD), and thus a signicantly lowered concentration of proteins in cell membranes and loss of function.
Currently, in my laboratory, we focus on studying:
- Gamma-aminobutyric acid type A (GABAA) receptors. They are the primary inhibiory ion channels in the mamalian central nervous systems. Loss of their function leads to idiopathic epilepies.
- Human Ether-a-go-go-Related Gene (hERG) channesl (gene name: KCNH2). Loss of their function leads to long-QT syndrome.
- GPI-anchored membrane proteins, whose function is associated with hypertension.
We explore how molecular chaperones, folding enzymes, ERAD factors, and trafficking factors, coordinate to facilitate membrane proein folding, degradation and trafficking.
We also use small molecule proteostasis regulators to correct misfolded membrane proteins, as a therapeutic strategy to treat corresponding diseases.
Proteostasis of membrane proteins
Membrane proteins maintain a delicate balance between protein synthesis, folding, trafficking and degradation. Mutant membrane proteins are subjected to excessive endoplasmic-reticulum associated degradation. Molecular chaperones and ERAD factors play a key role in regulating their proteostasis.
Understanding the Molecular Mechanism of Membrane Protein Folding and Degradation in Cells
Because the activity of membrane proteins is coupled to other proteins in complicated cellular interaction networks, the molecular mechanism of ion channel folding and degradation in the cell has been elusive. Using representative membrane proteins, we aim to reveal the protein homeostasis network that control their folding, degradation, and trafficking and thus function using proteomics, cell biology, electrophsiology, and animal model approaches.
Ameliorating Membrane Protein Misfolding Diseases.
We focus on diseases resulting from protein misfolding and thus reduced membrane protein surface expression and compromised function. This defective protein trafficking has been reported to result in many diseases, including neurodegenerative diseases and cardiovascular diseases.
We focus on developing multiple strategies to discover small molecules that enhance proper protein folding in cells to ameliorate diseases. We also explore the mechanism of action of these small molecules: how they alter the signaling pathways associated with the protein homeostasis network for disease intervention. Ultimately, we aim to develop novel therapeutic strategies for diseases associated with protein misfolding.
- Di XJ, Han, DY, Wang, YJ, Chance, MR, Mu, TW (2013) SAHA enhances proteostasis of epilepsy-associated α1(A322D)β2γ2 GABAA receptors. Chemistry and Biology, 20: 1456-1468
- Wang, YJ, Han, DY, Tabib, T, Yates, JR, and Mu, TW (2013) Identification of GABAC receptor protein homeostasis network components from three tandem mass spectrometry proteomics approaches. Journal of Proteome Research, 12: 5570-5586
- Ong DS, YJ Wang, YL Tan, JR Yates*, TW Mu* & JW Kelly*. FKBP10 depletion enhances glucocerebrosidase proteostasis in Gaucher disease fibroblasts. Chem. Biol. 20:403-15, 2013. * corresponding author
- Mu TW, DS Ong, YJ Wang, WE Balch, JR Yates, L Segatori & JW Kelly.Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell 134:769-81, 2008.
- Mu TW, HA Lester & DA Dougherty.Different binding orientations for the same agonist at homologous receptors: a lock and key or a simple wedge? J. Am. Chem. Soc. 125:6850-1, 2003.