Structure of Amino Acid Transporter Involved in Cancer Revealed
This is an image of the University of Groningen scientists involved in the study -- left to right, standing: D.J. Slotboom, A. Guskov, A.A. Garaeva, C. Paulino -- seated: G.T. Oostergetel. Credit: University of Groningen
The human glutamine transporter ASCT2 is upregulated in several forms of cancer. It is also the docking platform for a wide range of pathogenic retroviruses. A team of University of Groningen scientists have used cryo-electron microscopy to elucidate the structure of the protein, which may generate leads for drug development. The results were published in Nature Structural & Molecular Biology on 5 June.
In human cells, the ASCT2 protein imports the amino acid glutamine and maintains the amino acid balance in many tissues. The amount of ASCT2 is increased in several types of cancer, probably because of an increased demand for glutamine. Furthermore, several types of retrovirus infect human cells by first docking on this protein.
ASCT2 is part of a larger family of similar transporters. To understand how this family of amino acid transporters works, and to help design drugs that block glutamine transport by ASCT2 or its role as a viral docking station, University of Groningen scientists have resolved the 3D structure of the protein. They resorted to the technique of single particle cryo-electron microscopy, as they did not succeed in growing crystals from the protein, which are required for X-ray diffraction studies. The human gene for ASCT2 was expressed in yeast cells, and the human protein was purified for imaging.
The structure was determined at a resolution of 3.85 Å, which revealed striking new insights. 'It was a challenging target, as it is rather small for cryo-EM', says Assistant Professor of Structural Biology Cristina Paulino, who is head of the University's Cryo-EM unit. 'But it also has a nice symmetric trimeric structure, which helps.'
The cryo-EM images reveal a familiar type of 'lift-structure', in which part of the protein travels up and down through the cell membrane. In the upper position, substrate enters the lift, which then moves down to release the substrate inside the cell. The structure of ASCT2 revealed the lift in the lower position. 'To our surprise, this part of the protein was further down then we had ever seen before in similar protein structures', says Professor of Biochemistry Dirk Slotboom. 'And it was rotated. It had been thought that the substrate enters and leaves the lift through different openings, but our results suggest it might well use the same opening.'
This information could help design molecules that stop glutamine transport by ASCT2, says Albert Guskov, Assistant Professor in Crystallography. 'Some tests in mice with small molecules that block transport have been published.' Blocking glutamine transport would be a way to kill cancer cells. 'This new structure allows for a more rational design of transport inhibitors.'
Another surprise observation are the spikes that protrude on the outside of each of the three monomers. 'They have never been seen before', says Slotboom. 'These are the places where retroviruses dock.' This is consistent with mutagenic studies performed by others. Again, knowing the shape of the spikes could help design molecules which block the viruses from docking.
The protein structure was resolved in about four months, which is remarkably fast for cryo-EM. Different scientists, each with their own specialty, worked in parallel, which speeded up the process. Furthermore, PhD student Alisa Garaeva, who is first author of the paper, played a central role in ensuring the project ran efficiently.
Future studies will be done to capture ASCT2 in different configurations, for example inside a lipid bilayer rather than the detergent micelles used in the present study and with the lift in different positions. Paulino, Slotboom and Guskov conclude that studying different states will help them understand how this protein functions.
This article has been republished from materials provided by University of Groningen. Note: material may have been edited for length and content. For further information, please contact the cited source.
Cryo-EM Reveals Interaction Between Major Drug TargetsNews
For the first time, scientists have visualized the interaction between two critical components of the body's vast cellular communication network, a discovery that could lead to more effective medications with fewer side effects for conditions ranging from migraine to cancer.READ MORE
The Friedrich Schiller University Jena Partners with ACD/Labs to Advance its Analytical Data Management StrategyNews
Implementation of ACD/Spectrus as an analytical data management system helps researchers and students streamline NMR and MS data processing, interpretation, collaboration, and training.READ MORE
New Ovarian Cancer TargetNews
Researchers have found a prescription drug, Calcitriol, approved by the Food and Drug Administration for the treatment of calcium deficiency and kidney diseases, may increase the likelihood of surviving ovarian cancer. This new study opens a potential avenue for treating ovarian cancer. Since Calcitriol is an FDA-approved drug, no additional research is needed before the drug can advance to human clinical trials for ovarian cancer.READ MORE
Comments | 2 ADD COMMENT
clara micheal | Jun 10, 2018
PERFECT CURE FOR HERPES THAT WORK FAST WITHIN 14 DAYS WITH DR AZIBA HERBAL MEDICINE, I saw so many testimonies about Dr AZIBA a great HERBAL DOCTOR that will help you CURE and give you the rightful health to live a joyful life, i didn't believe it at first, but as the pain got worsen and my life was at risk after using lots pf drugs from the hospital and no changes so i decided to give a try to Dr AZIBA, I contacted him also and told him i want a cure for HERPES, he gave me advice on what i must do and he deliver it to me in my home address i gave him and i got the medicine which i use according to his instruction, and today i must say I am so grateful to this man Dr AZIBA for curing me from HERPES and for restoring me back to my normal health and a sound life and i am making this known to every one out there who have been trying all day to be cured from HERPES or any sickness should not waist more time just contact him with his details below, believe me this is the only way to get cured from HERPES, this is the real solution we all have been searching for. Do not waste more time contact him today for you can also leave a sound and happy life. contact info below. Email: Priestazibasolutioncenter@gmail.com or WhatsApp or Call him on: +2348100368288 and Website: http://drazibasolutioncenterworldwide.webs.com you can as well contact him on other issues you are having like HEPATITIS B,DIABETICS,CANCER,ALS, HIV,BODY REDUCTION AND Enlargement, FIBROD,CANCER,PREGNANCY, Relationship issues etc.. Email: Priestazibasolutioncenter@gmail.com
Daina Slim | Jun 08, 2018
Do anyone still doubt natural herbs? I''ve seen the great importance of natural herbs and the wonderful work they have done in people''s lives. I wonder why people still spend their hard earn money on injections and drugs each time they are sick. Natural herbs can cure herpes, diabetics, asthma, HIV, hepatitis, etc. I''ve seen it with my own eyes. i was cured of HIV by this herbalist doctor who uses natural herbs to cure different kind of illness. Even Dr. Camala prove to the whole world that natural herbs can cure all diseases/viruses and he cured countless of people using natural herbs. i know is had to believe but am a living testimony. If anyone here is sick, why not give it a try, there is no harm in trying. Contact Dr. Camala on: email@example.com whatsap no: +2349055637784