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Research findings of associate professor Zhang Wei, School of Pharmacy, are published in the sub-journal of Nature
Home  Research
Research findings of associate professor Zhang Wei, School of Pharmacy, are published in the sub-journal of Nature

As the joint first author, the Associate Professor Zhang Wei,School of Pharmacy, has cooperated with R&D Center for Ion Channel Drugs ofKunming Institute of Zoology of Chinese Academy of Sciences, ColumbiaUniversity and Tsinghua University to analyze the high-resolutionthree-dimensional structure of the important domain crystals of TRPML1 proteinsin the TRP channel family by comprehensive use of X-ray crystallography, frozenelectron microscopy, electrophysiology and other biochemical and physiological techniquesand revealed the regulatory mechanisms of physicochemical factors on TRPML1 andTRPML1 dysfunction as well as the direct correlation with MLIV-related genemutation. Research findings were published in Nature Structural & Molecular Biology (a sub-journal of Nature) and reached 13.338 in InfluenceFactor.

Lysosome is an ultrastructure which degrades various macromolecules(such as proteins and lipids) and recycles and reuses them. Its functional defectscan directly lead to abnormal storage of biomacromolecules and then affect thenormal function of cells and eventually result in disease. MLIV is a kind oflysosomal storage disease and its main symptoms consist of mental retardation,retinal degeneration, corneal opacity and iron and gastric acid deficiency. Thestudy found that TRPML1 gene mutation was a direct cause of MLIV. Therefore, itis very important to study its structure and function to understand thepathogenesis of MLIV, especially in lysosomes. With respect to problemsmentioned above, in order to understand the regulatory mechanisms of calciumion and acidic pH on TRPML1, Prof. Zhang Wei with a number of experts withinthe field has focused on the crystal structure and function of a long junctionfragment of I-II linker protein between I and II transmembrane fragments (TM1and TM2) of this channel. The experimental results show that this domain is arotating symmetric tetramer and forms a luminal pore with a diameter of 14A inthe center of tetramer, which is connected by a luminal pore ring composed of16 amino acid residues. The lysosome is rich in Ca+ (about 2 mM) and the proton(pH4.6) can competitively act on the pore and thus double regulate the activityof TRPML1 channel. In addition, the study also found that three MLIV pathogenicmutations altered the structure of this domain and led to an error inintracellular transport of TRPML1 channel proteins. This study provides astructural basis for understanding the regulation, assembly, function of TRPML1- an important protein and pathogenic molecular mechanisms of MLIV for thefirst time. It has important scientific significance and also provides a newidea for treatment of MLIV.

(Editor:admin Source:SCUN)