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Our research focuses on three main topics: ciliogenesis, parasitology, and membrane trafficking. Cilia and flagella are conserved organelles in most eukaryotes, which have attracted much attention in recent years because of their role in the transduction of extracellular signals and their association with an expanding number of human disorders. We have also been working on multiple large cytoskeletal protein complexes in human parasites including Trypanosoma brucei, Toxoplasma gondii, and Plasmodium. Membrane trafficking has been a long-lasting interest of us, for which we have focused mainly on vesicle targeting and membrane fusion.
The approaches we use to address the scientific questions include molecular biology, biochemistry, biophysics, structural biology, etc. We employ the three state-of-the-art structural study methods, X-ray crystallography, NMR spectroscopy and electron microscopy (EM), to determine 3D structures of target biological macromolecules. We also routinely use homology modeling, small angle X-ray scattering (SAXS), static/dynamic light scattering (SLS/DLS), circular dichroism (CD), isothermal titration calorimetry (ITC), and many other techniques in our studies. Our structural studies are often coupled with site-directed mutagenesis, in vitro biochemical experiments, and in vivo assays to validate our mechanistic hypotheses.
Gang Dong studied plant pathology in college and biophysics as a master’s student. After obtaining his PhD degree in 2002 from the University of Texas at Austin, he moved to work with Prof. Karin M. Reinisch at the Yale School of Medicine as a postdoc fellow working on membrane trafficking and antigen presentation. He was recruited to the Medical University of Vienna in 2008 to set up his own research group and appointed as the Head of the Division of Molecular Biology in August 2021.
CFAP410 is a ciliary protein essential for ciliogenesis. Multiple point mutations in human CFAP410 have been identified in patients with severe ciliopathies. Our recent structural studies on three diversified CFAP410 homologs (H. sapiens, C. reinhardtii & T. brucei) reveal that CFAP410 is a bimodular protein forming a unique homo-tetramer. Taking together our in vivo data, we could now provide an explanation how these mutations in CFAP410 cause human diseases (Stadler et al. 2022, bioRxiv).
The final step of exocytosis in budding yeast involves the assembly of two t-SNAREs, Sso1/2 and Sec9, with the v-SNARE Snc1/2. The rate-limiting step in this process is the initial formation of a binary complex of the two t-SNAREs. We just reported a new crystal structure of the pleckstrin homology (PH) domain of Sec3 (a component of the exocyt tethering complex) in complex with Sso2, which reveals a novel dual-site interaction between Sso2 and Sec3 that plays an essential role in promoting the fusion of secretory vesicles with the plasma membrane. (Peer et al. 2022, eLife).
Gorab is a well-known golgin at the trans-Golgi network. Interestingly, we found that it also localizes at the centriole to facilitate the assembly of the 9-fold symmetrical cartwheel of the centriole. Our studies reveal that Gorab dimers at the Golgi exist in equilibrium with Sas-6 associated Gorab monomers at the centriole to balance its dual role. (Fatalska*, Stepinac* et al. 2021, eLife).
As the sole site for all endo- and exocytosis in trypanosomes, the flagellar pocket (FP) is essential throughout the life cycle of the parasite.The FP is maintained by the flagellar pocket collar (FPC), which is a condensed cytoskeletal structure around the FP neck and essential for both FP biogenesis and cytokinesis. We recently identified the tripartite interaction among three FPC components (BILBO1, BILBO2 & FPC4) and furhter characterized the atomic details of the interaction between BILBO2 and FPC4. (Isch*, Majneri* et al. 2021, PLoS Pathog.).
E-Syts exist in many eukaryotes including yeasts, plants, and animals. They localize at the membrane contact sites between the ER and the plasma membrane to mediate inter-membrane lipid transfer. We have recently characterized a unique E-Syt from Trypanosoma brucei, which is distinct from all known E-Syts in several aspects. We propose a working model for how TbE-Syt tethers the ER membrane to the plasma membrane in T. brucei (Stepinac et al. 2021, iScience).
SET-domain lysine methyltransferases (KMTs) play key roles in regulation of gene expression in eukaryotes. We recently reported the structure of a novel dimeric KMT, the AKMT protein from the human parasite Toxoplasma gondii. Our work reveals that AKMT is the founding member of a new subclass of KMT and forms the basis for future therapeutic interventions (Pivovarova et al. 2018, J. Mol. Biol.).
We have reported the crystal structure of the t-SNARE Sso2 in complex with Sec3, a component of the exocyst complex that serves as a vesicle tether at the plasma membrane. Our work provides a mechanistic explanation for the initial step of vesicle fusion (Yue*, Zhang* et al. 2017, Nat. Commun.).
Polo-like kinase 4 (Plk4) has emerged as a master regulator of centriole duplication. We have reported crystal structures of the cryptic polo box of both Drosophila Plk4 and its C. elegans homolog ZYG-1. Our findings shed light on the conserved molecular mechanism underlying the recruitment of Plk4 and ZYG-1 to the nascent centriole (Shimanovskaya et al. 2014, Structure).
Trypanosoma brucei is the causative agent of sleeping sickness that threatens millions of African people. We have unraveled the architecture and assembly of a filamentous cytoskeletal protein named BILBO1, which acts as the scaffold of the flagellar pocket collar of T. brucei and is indispensable to its survival and pathogenicity (Vidilaseris et al. 2020, J. Biol. Chem.; 2014a, J. Biol. Chem.; 2014b, J. Biol. Chem.).
Centrioles play essential roles in both centrosome formation and cilium biogenesis. We have carried out structural studies on SAS-5 and SAS-6, two of the five core centriolar proteins. Our work uncovers the specific interaction between them and suggests a mechanism for them to cooperatively facilitate the correct assembly of the 9-fold symmetric centriole (Qiao et al. 2012, EMBO J.).
(Last five years only)
Double NPY motifs at the N-terminus of the yeast t-SNARE Sso2 synergistically bind Sec3 to promote membrane fusion.
Peer, Maximilian; Yuan, Hua; Zhang, Yubo; Korbula, Katharina; Novick, Peter; Dong, Gang
Structural studies of the shortest extended synaptotagmin with only two C2 domains from Trypanosoma brucei
Stepinac, Emma; Landrein, Nicolas; Skwarzynska, Daria; Wójcik, Patrycja; Lesigang, Johannes; Lu?i?, Iva; He, Cynthia Y; Bonhivers, Mélanie; Robinson, Derrick R; Dong, Gang
Structural and functional studies of the first tripartite protein complex at the Trypanosoma brucei flagellar pocket collar.
Isch, Charlotte; Majneri, Paul; Landrein, Nicolas; Pivovarova, Yulia; Lesigang, Johannes; Lauruol, Florian; Robinson, Derrick R; Dong, Gang; Bonhivers, Mélanie
The dimeric Golgi protein Gorab binds to Sas6 as a monomer to mediate centriole duplication.
Fatalska, Agnieszka; Stepinac, Emma; Richter, Magdalena; Kovacs, Levente; Pietras, Zbigniew; Puchinger, Martin; Dong, Gang; Dadlez, Michal; Glover, David M
Structure of a Novel Dimeric SET Domain Methyltransferase that Regulates Cell Motility.
Pivovarova, Yulia; Liu, Jun; Lesigang, Johannes; Koldyka, Oliver; Rauschmeier, Rene; Hu, Ke; Dong, Gang
Sec3 promotes the initial binary t-SNARE complex assembly and membrane fusion.
Yue, Peng; Zhang, Yubo; Mei, Kunrong; Wang, Shaoxiao; Lesigang, Johannes; Zhu, Yueyao; Dong, Gang; Guo, Wei
Project title: "Structural basis of tRNA synthetase-based selfish killer" (P 34880)
A new grant was freshly approved by the FWF on 10 May, 2021! This grant (Sum: 603,960.00 EUR) will support the collaborative work between Dr. Alejandro Burga’s group (IMBA, VBC) and us on eukayrotic Selfish Elements, which underlie numerous cases of hybrid dysgenesis, sterility and genetic incompatibilities in nature. We will use our complementary expertise in genetics and structural biology to dissect the molecular mechanism of a set of selfish elements in the nematodes C. elegans and C. tropicalis.
Duration: 01 July, 2021 - 30 June, 2025.
Project title: "Mechanism of infectivity acquisition in African trypanosomes" (2 R01 AI110325-06)
A newly approved NIH-R01 grant ($345,724.00; total: $2,311,805.00) to support our collaborative work with Prof. Christian Tschudi's group at the Yale School of Medicine to unveil the molecular mechanism of the infectivity acquisition in African Trypanosomes. Our complementary expertise will provide unique opportunities for us to illuminate the developmental program leading from non-infective procyclics to infectious metacyclics, a crucial process in the T. brucei life cycle.
Duration: 01 Mar, 2019 - 29 Feb, 2024.
Project title: "Why and how trypanosomes build a flagellar pocket collar" (I 4960-B)
In collaborataion with Dr. Melanie Bonhivers from the University of Bordeaux and co-funded by the FWF (Austria) and the ANR (France). The grant (Sum: 705,485.70 EUR) will support our joint effort to study the flagellar pocket collar (FPC) of the human parasite Trypanosoma brucei. We aim to explain how a new FPC is formed, why it is essential, what polymers/proteins are needed, and how they interact.
Duration: 01 Oct, 2020 - 30 Sept, 2024.
The Group Dong participated in and was one of the seven full members of the Doctoral Program "Integrative Structural Biology" (W-1258), which was reviewed and funded by the Austrian Science Fund FWF.
Duration: 01 Jan, 2016 - 30 June, 2020.
Project title: “Structural Characterization of ZYG-1 in Centriole Assembly" (P 28231)”
Duration: 01 July, 2015 - 30 June, 2020.
Project title: “Structural studies of the Trypanosoma brucei protein TbBILBO1" (P 24383-B21)
Duration: 01 May, 2012 - 30 Apr, 2016.
Project title: “Structural Studies of the Intraflagellar Transport Complexes" (P 23440-B20)
Duration: 01 Apr, 2011 - 31 Oct, 2015.
Project title: "Towards sustainable food and bioenergy security for society: Establishing an academic compound screening platform in Vienna to characterize and modulate Strigolactone synthesis in plants" (WWTF 2009) Role: Research Partner (PI: Dr. T. Sieberer). Duration: 2011 - 2014.