| Project Id
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BITS025F001454
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| Project Detail
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| Project Title
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Structure-Function Relationship of a Flippase-conjugated Guanylate Cyclase in Toxoplasma gondii
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| Senior Supervision Team (BITS)
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| Supervisor name and Title
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Nishith Gupta, Professor
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School or Department (or company, if applicable)
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BITS PILANI, HYDERABAD CAMPUS
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Email ID
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gupta.nishith@hyderabad.bits-pilani.ac.in
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| URL for more info
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https://universe.bits-pilani.ac.in/Hyderabad/guptanishith/Profile
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| a) Are you currently supervising a BITS or RMIT HDR student?
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YES
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| Please comment how many you are supervising
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10
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| b) Have you supervised an offshore candidate before?
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YES
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| If no, what support structures do you have in place?
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|
| If yes, please elaborate
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| Senior Supervision Team (RMIT)
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| Supervisor name and Title
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Natalie Borg
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School or Department (or company, if applicable)
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STEM
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Email ID
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natalie.borg@rmit.edu.au
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| URL for more info
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rmit.edu.au/natalieborg-lab
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| a) Are you currently supervising a BITS or RMIT HDR student?
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NO
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| Please comment how many you are supervising
|
|
| b) Have you supervised an offshore candidate before?
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NO
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| If no, what support structures do you have in place?
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|
| If yes, please elaborate
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N
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| Other Supervisors (BITS)
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| Supervisor name and Title
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Ratnesh Kumar Srivastav, Dr.
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School or Department (or company, if applicable)
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BITS PILANI, HYDERABAD CAMPUS
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| Phone Number (Optional)
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8448477654
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Email ID
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ratnesh@hyderabad.bits-pilani.ac.in
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| URL for more info
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| Other Supervisors (BITS)
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| Supervisor name and Title
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Dr Charlett Giuliani
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School or Department (or company, if applicable)
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STEM
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| Phone Number (Optional)
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Email ID
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charlett.giuliani@rmit.edu.au
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| URL for more info
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| Field of Research (For Codes)
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| 060112 | Structural Biology (incl. Macromolecular Modelling | 50.00 |
| 310407 | Host-Pathogen Interaction | 25.00 |
| 320704 | Medical Parasitology | 25.00 |
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| Project Description
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|
The architecture and functioning of cGMP signaling is well characterized in metazoans, but poorly understood in protozoans. Some intracellular parasitic protists harbor chimeric proteins embodying P4-type ATPase and guanylate cyclase domains. Such proteins – the actuator of physiologically-essential and druggable cGMP signaling in this group of clinically relevant important pathogens – are unusual in their sheer size, modus operandi, and evolutionary repurposing. Much like the mythological Sphinx, a human-lion chimeric creature that posed challenging riddles, the P4-type ATPase–guanylate cyclase chimeras present structural and functional conundrums. In this project, we combine the expertise of two PIs and two co-PIs at BITS-RMIT to address the function, topology, mechanism, and intramolecular coordination of the flippase-conjugated guanylate cyclase from the model protozoan pathogen Toxoplasma gondii. We will express and purify the functional domains in bacterial and mammalian systems and then crystallize them to resolve the mechanism and functionality of this protein. In parallel, we will also aim to perform structure determination of the native protein in complex with interaction partners isolated from T. gondii.
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| Project Deliverable/Outcomes
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Our results will resolve long-standing questions about the mechanism of signal sensing and integration and the actuation of cGMP and lipid signaling in a medically-important model intracellular pathogen. Given the high clinical importance, cGMP signaling and phospholipid flipping have been distinct research topics studied in their own context. The unexpected fusion of atypical guanylate cyclase with a P4-ATPase in alveolates shows a remarkable example of their functional coupling in protists. Moreover, the GC domains of protozoan ATPasep–GC chimeras are related to the G-protein-dependent adenylate cyclases instead of classical GCs, which would signify the evolutionary repurposing of the enzyme. Last but not least, a uniquely designed signaling platform (CDC50–ATPasep–GC–UGO) in the plasma membrane – presumably conserved across the apicomplexan clade – opens the door for innovative tools (e.g., crystallography, AFM, cryoelectron microscopy, cGMP biosensors, optogenetics) to understand cGMP signaling and lipid flipping entirely. A major outcome of the collaboration will be the training of the PhD student from BITS in cutting-edge structural biology approaches at RMIT.
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| Research Impact Themes
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| BETTER HEALTH OUTCOMES | AFFORDABLE HEALTH AND PREVENTABLE DISEASES |
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| Which RMIT Sustainable Development Goal (SDG) does your project align to
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GOOD HEALTH AND WELLBEING
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| Which RMIT Enabling Impact Platform (EIP) does your project align to
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BIOMEDICAL AND HEALTH INNOVATION
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| Which RMIT Program code will this project sit under?
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DR231 (BIO)
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| Student Capabilities and Qualifications
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Biological Sciences, English Skills, Strong Motivation
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Structure Biology, Molecular Parasitology, Genome Engineering
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MSc or MTech
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| Preferred discipline of Student
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| Biological Sciences |
| Biology, Cell Biology, Niological Sciences |
| Biomedical Sciences |
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