个人简介

B.S., 1999, Peking Univ. Ph.D., 2004, Peking Univ.

研究领域

Biological Inorganic Physical

(Research Description PDF - 1169 kb) Metal transportation across cell membranes is an essential process in metal utilization in our body. This work is conducted by a variety of membrane proteins, including ion channels, pumps and transporters. Homeostasis of microelements, such as iron, zinc and cooper, is mainly regulated by their specific transporter proteins. Our research is focusing on metal transporters important in medicine. Our goal is to clarify the structure/function relationship of these membrane proteins by applying multidisciplinary approaches, including x-ray crystallography, NMR and other biochemical/biophysical methods, as well as cell-based functional studies. Our efforts will eventually benefit human health and our environment. Currently, we are interested in two proteins involved in iron and zinc transportation, respectively (Fig. 1). Divalent Metal Transporter 1 (DMT1) is a central player in iron homeostasis. It is responsible for non-heme iron uptake from dietary food, and it is also essential for iron uptake by most of cells through the transferrin cycle. Missense mutations on human DMT1 result in severe iron metabolism disorders. DMT1 is also implicated in abnormal iron accumulation in the brain often observed in severe neurodegenerative diseases (Alzheimer’s disease and Parkinson’s disease). The specific aim of our structural biological research on DMT1 is to decipher the molecular mechanism of proton-coupled iron transportation. Zrt- and Irt-like protein 4 (ZIP4) plays essential roles in zinc absorption from the intestine and reabsorption in the kidney. Acrodermatitis enteropathica (AE), an autosomal recessive human disease with typical symptoms of zinc deficiency, is caused by missense mutations on ZIP4. Many of these mutations are located on the large extracellular domain (ECD), whereas it is unknown how these mutations on ECD influence the protein function. Our aim is to determine the mechanism of zinc transportation through ZIP4 with a particular emphasis on the structure and function of ZIP4 ECD. Fig.1. Topology of DMT1 and ZIP4 in membrane. Fig.2. PIP5K phosphorylates PI(4)P to PI(4,5)P2. Activation of PIP5K by its binding partners is a crucial step in endocytosis, as PI(4,5)P2 functions as a co-receptor to recruit endocytic proteins to plasma membrane. Endocytosis is an indispensable step in both transferrin cycle and ZIP4 function regulation. Out of many proteins involved in this complicated process, we are particularly interested in a lipid kinase, phosphatidylinositol 4-phosphate 5-kinase (PIP5K). PIP5K is a peripheral membrane protein and generates an important signaling lipid molecule, PI(4,5)P2, which recruits cytosolic proteins essential in endocytosis to plasma membrane and regulates their functions. Recently, we have solved the crystal structure of the kinase catalytic domain of PIP5K from zebra fish. Now we are making efforts to clarify the molecular mechanism of PIP5K regulation by its binding partners in endocytosis (Fig. 2).

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The Crystal Structure of GxGD Membrane Protease FlaK, Jian Hu, Yi Xue, Sangwon Lee and Ya Ha, Nature 2011, 475, 528-531. A Systematic Assessment of Mature MBP in Membrane Protein Production: Overexpression, Membrane Targeting and Purification, Jian Hu, Huajun Qin, Fei Philip Gao and Timothy A. Cross, Protein Expression & Purification 2011, 80(1), 34-40. The E2 Domains of APP and APLP1 Share a Conserved Mode of Dimerization, Sangwon Lee, Yi Xue, Jian Hu, Yongcheng Wang, Xiuying Liu, Borries Demeler and Ya Ha, Biochemistry 2011, 50(24), 5453-5464. Ligands Binding on the Interhelical Loop of CorA, a Magnesium Transporter from Mycobacterium Tuberculosis, Jian Hu, Mukesh Sharma, Huajun Qin, Fei Philip Gao and Timothy A. Cross, Journal of Biological Chemistry 2009, 284(23), 15619-15628. Construction of a Series of Vectors for High Throughput Cloning and Expression Screening of Membrane Proteins from Mycobacterium tuberculosis, Huajun Qin, Jian Hu, Yuanzhi Hua, Shridhar Venkata Challa1, Timothy A. Cross and Fei Philip Gao, BMC Biotechnology 2008, 8(1), 51.