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Qingshan (Bill) Fu, Ph.D. Professor, Principle Investigator, Mentor of Ph.D. students. In the year 2002, graduated from Shandong Normal University, got the Bachelor’s degree in Biology. In July 2005, got Master’s degree in Bioinformatics. In 2006, Qingshan joined Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences and worked on Protein Aggregation and Ubiquitin induced protein degradation in Hongyu Hu’s lab. Graduated in July 2010, got Ph.D. in Biochemistry and Molecular Biology. During January 2011 to December 2018, Qingshan worked as a Postdoc in James Chou Lab in Harvard Medical School. Using solution NMR method solved the first transmembrane trimer structure of TNFR family receptors. Solved the membrane adjacent region of HIV1 gp41 structures. January 2019 to September 2021, Qingshan was assigned the Instructors position and worked on HIV envelope protein and SARS-COV2 spike protein, and screening for drugs to inhibit virus infection. Now, Qingshan becomes a Principle Investigator in Shanghai Institute of Materia Medica.

NMR, membrane protein structure, Anti-virus drug mechanism.

Longevity and relations to neuro-endocrine metabolism regulation.

Qingshan have long standing interest in the structure and functional roles of the transmembrane (TM) and membrane-proximal regions of cell surface proteins. Historically, these regions of the receptors occupy the ‘blind spot’ in structural biology because they are usually too hydrophobic and dynamic for crystallization and too small for cryo-EM. He realized the unique position of high-resolution NMR to generate structural information to fill these structural gaps. He thus determined to innovate NMR/Biochemistry approaches to tackle the lingering functional and structural questions associated with the membrane regions of signaling receptors, viral fusion proteins, as well as bacterial environmental sensing proteins.

Years of persistent endeavor and collaboration with colleagues at Harvard eventually came to fruition in 2016, when he unveiled the atomic resolution structure of the TM domain of the Fas death signaling receptor, a classic member of the large tumor necrosis factor receptor (TNFR) superfamily. In this study, he found a way to reconstitute human Fas TM domain in bicelles that mimic a ~65 ？ lipid disc, and then determined a high resolution structure using the state-of-the-art NMR methods. The structure shows that the Fas TM helix trimerizes in membrane via a novel proline structural motif; it also represents the first structure of a TM helix trimer. The significance of my finding is that the TM helix trimerization is essential for receptor activation, a concept that subsequently led to a new discovery in the lab that the TM helices of some immunoreceptors not only play the critical function of receptor assembly but also mediate higher order receptor cluster to drive signaling. These exciting new developments in receptor biology, which stemmed from by original Fas TM structure, have highlighted the important application of NMR in membrane biology.

His work on the membrane regions of TNFRs captured interests from many colleagues at Harvard, and two of them were Bing Chen and Stephen Harrison, who have been trying for decades to determine the structure of the membrane region of the HIV-1 envelope glycoprotein (Env). The HIV Env is the sole antigen used for B-cell based vaccine development. Bing and Steve found that mutagenesis or deletions that destabilize the membrane region of the Env could drastically alter antibody binding to the Env ectodomain on the opposite side of the membrane, suggesting that the membrane region is well structured so that it could mediate the physical coupling across the membrane. But, they have not yet succeeded in obtaining any structural information for this region after many years of attempts using crystallography and cryo-EM. The goal was to provide the structure of the membrane region to guide the design of the next generation HIV-1 immunogen that can better induce neutralizing antibodies.

In the project, He first played a pivotal role in developing the bicelle-based sample system for the TM domain of HIV-1 Env, which eventually led to the high-resolution NMR structure of the TM helix trimer. He then took a step further to determine the structure of the membrane-proximal external region (MPER) of the Env in the prefusion state. The MPER is the most conserved region of the Env and contains the epitopes of several broadly neutralizing antibodies isolated from HIV-infected patients. Based on our new TM and MPER structures, he had already designed a series of new immunogens (unidirectionally presented envelope proteins on nanobodies) currently being tested in guinea pigs and monkeys.

Finally, He prepared a review article that summarizes, in details, the NMR and biochemistry protocols he developed in James Chou’s lab for studying the transmembrane and membrane-proximal regions of cell surface proteins. He found many important immune receptors contain TM sequence that is likely to dimerize, trimerize, or even form higher order dimer-trimer network. For example, several members of the TNFR superfamily such as OX40 and 4-1BB have unusual TM sequences that may lead to more surprising findings about their activation. Further, the membrane regions of many viral fusion proteins other than the ones from HIV also have very interesting sequences that I expect to adopt unusual structures.  More recently, he came across another fascinating class of TM receptors known as the two-component system of bacteria, which play important roles in sensing all kinds of environmental factors such as cellular cytokines, osmotic pressure, pH, membrane curvature, etc. These receptors all have a small TM domain consisting of two TM helices. He envisage that my NMR and biochemistry protocols can be broadly applied to investigate all of these interesting systems for which detailed structural information of the membrane regions are unknown.