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Zhu Jinwei’s Team Published Research Findings in PNAS and Cell Reports

March 12, 2021      Author:

 

Recently, the research team led by associate professor Zhu Jinwei from Bio-X Research Institute of SJTU and the team led by Wang Zhao from School of Life Sciences of the University of Science and Technology of China published a collaborative research article titled “Double inhibition and activation mechanisms of Ephexin family RhoGEFs” in Proceedings of the National Academy of Sciences (PNAS). This study has found that association of PDZ proteins and phosphorylation of a conserved tyrosine residue in its amino-terminal polypeptide sequence “LYQ” can relieve the autoinhibitory modes of the carboxy-terminus and the amino-terminus respectively (Figure 1). This finding offers a reliable structural explanation for the pathological dysfunction of related neurological diseases and tumors.

Figure1. Double autoinhibition and activation mechanisms of Ephexin4

Meanwhile, Zhu Jinwei’s team and Zhang Rongguang’s team from the Institute of Biochemical Cells of the Chinese Academy of Sciences published another collaborative research on the website of Cell Reports, titled “Phase Separation-mediated Condensation of Whirlin-Myo15-Eps8 Stereocilia Tip Complex”. This research, for the first time, reveals the molecular mechanism of liquid-liquid phase separation mediating the formation of the apical complex of stereocillia, which provides a new theoretical perspective for elucidating TCD-induced development and the pathogenesis of related hearing loss. 

 

Figure2. Liquid-liquid phase separation mediates the formation of the apical complex of stereocillia

 

Outstanding students are welcome to join the team, explore the fun of research and decode the mysteries of life.

Contact: jinwei.zhu@sjtu.edu.cn

 

 

 

SourceBio-X Research Institute, SJTU

Translated by Zhang Yue

Proofread by Xiao Yangning, Fu Yuhe

 

“Double Inhibition and Activation Mechanisms of Ephexin Family RhoGEFs”

 

ABSTRACT:

Ephexin family guanine nucleotide exchange factors (GEFs) transfer signals from Eph tyrosine kinase receptors to Rho GTPases, which play critical roles in diverse cellular processes, as well as cancers and brain disorders. Here, we elucidate the molecular basis underlying inhibition and activation of Ephexin family RhoGEFs. The crystal structures of partially and fully autoinhibited Ephexin4 reveal that the complete autoinhibition requires both N- and C-terminal inhibitory modes, which can operate independently to impede Ras homolog family member G (RhoG) access. This double inhibition mechanism is commonly employed by other Ephexins and SGEF, another RhoGEF for RhoG. Structural, enzymatic, and cell biological analyses show that phosphorylation of a conserved tyrosine residue in its N-terminal inhibitory domain and association of PDZ proteins with its C-terminal PDZ-binding motif may respectively relieve the two autoinhibitory modes in Ephexin4. Our study provides a mechanistic framework for understanding the and offers possible clues for its pathological dysfunction.

 

“Phase Separation-mediated Condensation of Whirlin-Myo15-Eps8 Stereocilia Tip Complex”

 

SUMMARY:

Stereocilia, the mechanosensory organelles on the apical surface of hair cells, are necessary to detect sound and carry out mechano-electrical transduction. An electron-dense matrix is located at the distal tips of stereocilia and plays crucial roles in the regulation of stereocilia morphology. Mutations of the components in this tip complex density (TCD) have been associated with profound deafness. However, the mechanism underlying the formation of the TCD is largely unknown. Here, we discover that the specific multivalent interactions among the Whirlin-myosin 15 (Myo15)-Eps8 complex lead to the formation of the TCD-like condensates through liquid-liquid phase separation. The reconstituted TCD-like condensates effectively promote actin bundling. A deafness-associated mutation of Myo15 interferes with the condensates formation and consequently impairs actin bundling. Therefore, our study not only suggests that the TCD in hair cell stereocilia may form via phase separation but it also provides important clues for .