“Hard work on interesting problem is enjoyable and preferable to aimless wasting of leisure time. It may also lead to unexpected findings that give insights into important related problems. Such unexpected findings-some time called “luck”-frequently happen to the active researcher, but only rarely to those who prefer talk to study and work. So one should study and work hard, on interesting problems of any nature, with the purpose of explaining nature and helping others—Esmond Snell ”
Biography
Dr. Xiaoming Zhou obtained his bachelor’s and master’s degrees from Lanzhou University in 2008 and 2011, respectively. In 2015, He received his Ph.D. degree from the Institute of Biophysics, Chinese Academy of Sciences. In 2016, he joined in Dr. Steven McKnight’s lab at UT Southwestern Medical Center and worked as a postdoctoral researcher for four years, after which, he was promoted to a position of instructor. His research interest is mechanistically understanding how protein low complexity domains operate in physiology and disease. In 2023, he will join Westlake University as an assistant professor.
Research
Protein low complexity domains (LCDs) that lacking in predictable three-dimensional structures and functions, are a widespread feature of the human proteome and are closely associated with human diseases, including cancers and neurodegenerative diseases. Despite their prevalence and clinical relevance, the lack of assays and techniques to study LCDs has left the molecular mechanism of their physiological function and transition to disease-associated state an enigma.
By developing assays and techniques specialized for mechanistically studying protein LCDs, we found that LCDs use relatively short motifs to mediate protein self-association via specific, regulated, and labile cross-beta interactions. Importantly, we have shown that this homo-oligomerization mechanism is required for proper organization of subcellular structures, including intermediate filaments and membraneless organelles/biomolecular condensates. These findings led us to the discovery that many recurrent missense mutations causative of human disease directly stabilize otherwise transient cross-beta interactions, thus facilitating transition to disease-associated structure.
In the future, we will keep trying to mechanistically understand: (i) how the cell integrates homotypical and heterotypical LCD interactions to organize functionally specific cellular assemblies, (ii) the molecular basis for LCD interaction specificity, and (iii) how these interactions are altered in disease-causing human diseases, particularly in neurological disease and cancer. Ultimately, these mechanistic insights may guide the development of strategies to manipulate LCD interactions in laboratory and clinical settings.
Representative Publications
1. Zhou, X.M., Sumrow L., Tashiro K., Sutherland, L., Liu D., Qin T., Kato M., Liszczak, G., McKnight, S.L. Mutations linked to neurological disease enhance self-association of low complexity protein sequences. Science (2022) 377(6601)
Highlighted by the perspective “Petsko, G.A., and Small, S.A. Elucidating the causes of neurodegeneration. Science (2022) 377.”
2. Zhou, X.M., Lin, Y., Kato, M., Mori, E., Liszczak, G., Sutherland, L., Sysoev, V. O., Murray, D. T., Tycko, R., & McKnight, S. L. Transiently structured head domains control intermediate filament assembly. PNAS (2021) 118(8).
Highlighted by the perspective “Faridounnia, M., and Snider, N.T. Assembly of NFL and desmin intermediate filaments: Headed in the right direction. Proc Natl Acad Sci U S A (2021) 118.”
3. Kato, M., Zhou, X.M., and McKnight, S.L. How do protein domains of low sequence complexity work? RNA (2022). 28, 3-15.
4. Lin, Y., Zhou, X.M., Kato, M., Liu, D., Ghaemmaghami, S., Tu, B.P., and McKnight, S.L. Redox-mediated regulation of an evolutionarily conserved cross-beta structure formed by the TDP43 low complexity domain. PNAS (2020) 117, 28727-28734.
5. Murray, D.T., Zhou, X.M., Kato, M., Xiang, S., Tycko, R., and McKnight, S.L. Structural characterization of the D290V mutation site in hnRNPA2 low-complexity-domain polymers. PNAS (2018)115, E9782-E9791.
Contact Us
zhouxiaoming@westlake.edu.cn