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|
| Type |
Symposium |
| Area |
Structure and Function of Membrane Proteins |
| Room No. |
Room 314 |
| Time |
THU 15:40-: |
| Code |
LIFE1-1 |
| Subject |
The functional role of Frizzled4 linker domain in Norrin signaling pathway |
| Authors |
Hee-Jung Choi
Department of Biological Sciences, Seoul National University, Korea |
| Abstract |
Frizzled (Fzd) is a main receptor for Wnt ligand and the ligand binding to Fzd is a crucial part of Wnt signaling pathway. Published structural studies of Fzd focus on the ligand binding domain of Fzd, called cysteine-rich domain (CRD). CRD in complex with Wnt or Norrin have revealed much information on the molecular interaction between CRD and ligand. However, the question remains how that interaction with ligand is transferred across the transmembrane domain (TMD) to the intracellular region. All 10 members of Fzd family have relatively high sequence conservation in the TMD, while the extracellular and C-tail regions have low conservation. Especially of interest is the linker domain between CRD and TMD, which varies from about 40 amino acids in Fzd4 to 100 amino acid in Fzd8. Here, we show that a flexible linker domain, which connects the CRD to the TMD of Fzd4, plays an important role in Norrin signaling. The linker domain directly contributes to the high-affinity interaction between Fzd4 and Norrin as shown by ~10-fold higher binding affinity of Fzd4CRD to Norrin in the presence of the linker. In addition, structural dynamics of Fzd4 associated with Norrin binding investigated by hydrogen/deuterium exchange MS revealed Norrin-induced conformational changes on the linker domain and the intracellular loop 3 (ICL3) region. Together, our results show that the linker domain plays an important role in Norrin ligand recognition, thereby its signal transmission from extracellular to intracellular regions. |
| E-mail |
choihj@snu.ac.kr |
|
122nd General Meeting of the KCS