Tag Archives: #protein

This Protein Is Highly Potent In Blocking SARS-CoV-2 (Biology)

Recep Ahan and colleagues evaluated the activity of griffithsin lectin protein (GRFT) from Griffithsia sp. against the novel human coronavirus, SARS-CoV-2. They demonstrated that this protein can not only block the entry of the Sars-CoV-2 but also inhibit its infection by attaching to spike protein of the Sars-CoV-2, both in vitro VeroE6 cell line and in vivo mouse model. Their study recently appeared in BioRxiv.

Lectin proteins isolated from seaweeds are shown to be potent antiviral agents against enveloped viruses e.g., HIV-1, herpes virus as well as two deadly human coronaviruses, SARS-CoV and MERS-CoV. Antiviral activity of seaweed lectins arises from their affinity to surface glycoproteins on viruses such as gp-120 protein of HIV-1 and spike proteins of SARS-CoV and MERS-CoV. Upon binding to surface proteins, lectins generally block the viral internalization step and thereby prevent the viral infection.

Now, Recep Ahan and colleagues evaluated the activity of griffithsin lectin protein (GRFT) from Griffithsia sp. against the novel human coronavirus, SARS-CoV-2.

Schematic representation of rGRFT inhibiting SARS-CoV-2 infection in Vero E6 cells. Created with BioRender.com © authors

For this purpose, they recombinantly expressed GRFT in E. coli with histidine tag and purified. Later, they validated and characterized binding of recombinant GRFT to whole inactivated SARS-CoV-2 as well as purified spike protein from HEK293 with the help of ELISA, ITC and QCM. Finally, they assessed the activity of GRFT in vitro with Vero6 cells, and in vivo with Syrian hamsters.

They demonstrated that griffithsin protein from Griffithsia sp. recombinantly produced in E. coli can bind spike (S) protein of SARS-CoV-2 in vitro and inhibit its infection both in vitro VeroE6 cell line and in vivo mouse model when applied prophylactically. In addition, toxicity assays of rGRFT with mouse models indicated that, it is a tolerable agent even at concentrations higher than its therapeutic concentration window.

“Our results indicate that GRFT is a potent non-mutagenic antiviral agent against SARS-CoV-2, reducing virus transmission through blocking its entry into the cells.”

— they said.

Finally, upon very promising results from in vitro and in vivo assays and experiments, they formulated GRFT as a nasal spray for upcoming human phase trials.

“We believe that GRFT protein-based drugs will have a high impact in preventing the transmission both on Wuhan strain as well as any other emerging variants including delta variant causing high speed spread of COVID-19.”

— they concluded.

Reference: Recep Erdem Ahan, Alireza Hanifehnezhad, Ebru Şahin Kehribar, Tuba Cigdem Oguzoglu, Katalin Földes, Cemile Elif Özçelik, Nazlican Filazi, Sıdıka Öztop, Sevgen Önder, Eray Ulaş Bozkurt, Koray Ergünay, Aykut Özkul, Urartu Özgür Şafak Şeker, “A Highly Potent SARS-CoV-2 Blocking Lectin Protein”, bioRxiv 2021.07.22.453309; doi: https://doi.org/10.1101/2021.07.22.453309


Note for editors of other websites: To reuse this article fully or partially kindly give credit either to our author/editor S. Aman or provide a link of our article

Plant-Based Diets Support Muscle Gain and Strength (Food)

Plant-based diets support muscle mass gain among young adults, according to a study published in Sports Medicine. Researchers compared protein intake and leg muscle mass in young men who followed either a vegan diet or an omnivorous diet as part of a twice-weekly resistance training program. Vegan participants took soy protein isolate supplements while nonvegan participants supplemented protein intake with whey (dairy) protein supplements. All participants increased muscle mass with no differences between the diet groups. These results suggest protein source does not affect muscle gain among young men with adequate protein intake.

Featured image credit: Getty images


Reference

Hevia-Larraín V, Gualano B, Longobardi I, et al. High-protein plant-based diet versus a protein-matched omnivorous diet to support resistance training adaptations: a comparison between habitual vegans and omnivores. Sports Med. 2021;51(6):1317-1330. doi: 10.1007/s40279-021-01434-9


Provided by Physicians Committee for Responsible Medicine

Antioxidant Protein Inside the Cell Worsens Inflammation Outside (Medicine)

New role for DJ-1 suggests a potential target for acute stroke treatment

A protein that provides essential protection against free radicals inside the cell provokes damaging inflammation when released outside, activating immune cells and worsening damage following a stroke, according to a new study published 20th May, 2021 in the open access journal PLOS Biology by Takashi Shichita of the Tokyo Metropolitan Institute of Medical Science and colleagues.

The protein DJ-1 acts within cells to mop up dangerous molecular fragments called free radicals. It is thought to prevent neurodegeneration by reducing oxidative stress within aging neurons; indeed, an inactivating mutation in the gene that encodes DJ-1 causes one form of Parkinson’s disease (DJ-1 is also known as PARK7 for this reason).

When a cell ruptures, its contents are released into the surroundings, where certain released molecules, called DAMPs (damage-associated molecular patterns) act as alarm signals to activate inflammatory processes, including the attraction of macrophages to clean up the damage. At low levels and for short periods of time, inflammation in the brain can be beneficial. But when the damage is extensive, as in stroke, inflammation can contribute to the problem rather than the solution.

To identify new DAMPs, the authors prepared brain homogenates and then separated the proteins within by molecular weight. They had previously shown that one subset, between 15 and 25 kilodaltons, contained DMAP activity. Here, they identified candidate proteins within that subset by using mass spectrometry, generated the purified proteins, and then added them to cultured macrophages.

One of those proteins was DJ-1, which prompted upregulation of inflammatory cytokines in the macrophages. The researchers showed that this effect was triggered by interaction with Toll-like receptors on the surface of macrophages, membrane proteins known to mediate inflammatory activation. To further confirm DJ-1’s pro-inflammatory potential, the team showed that its DAMP activity depended on the presence of two key sections of the protein’s three-dimensional structure; altering these abolished the effect. Finally, they showed that DJ-1 was released by dying cells during stroke in a mouse model, and that knocking out DJ-1, or blocking it with an antibody, reduced the damage caused by stroke.

“Extracellular DJ-1 is a previously unknown inflammatogenic DAMP,” said Shichita, “and may be a putative target for therapeutic intervention to prevent the progression of inflammatory and neurodegenerative diseases.”

Dr. Shichita notes “DJ-1 has been thoroughly investigated as a cytoprotective antioxidant protein in neurons. However, here we demonstrate that extracellularly released DJ-1 triggers neurotoxic inflammation after ischemic stroke. Intracellular DJ-1 increases in response to oxidative stress in ischemic neurons, but if ischemic stresses result in necrotic cell death, DJ-1 is passively released into the extracellular space. Released DJ-1 interacts with Toll-like receptor 2 (TLR2) and TLR4 in the infiltrating myeloid cells and triggers post-ischemic inflammation, leading to the exacerbated pathologies of ischemic stroke. Thus, extracellular DJ-1 is a previously unknown inflammatogenic DAMP, and may be a putative target for therapeutic intervention to prevent the progression of inflammatory and neurodegenerative diseases.”

In your coverage please use these URLs to provide access to the freely available articles in PLOS Biologyhttp://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.300093

Featured image: Schematic model of the roles of DJ-1 in the ischemic brain injury. © Takashi Shichita, CC0


Reference: Nakamura K, Sakai S, Tsuyama J, Nakamura A, Otani K, Kurabayashi K, et al. (2021) Extracellular DJ-1 induces sterile inflammation in the ischemic brain. PLoS Biol 19(5): e3000939. https://doi.org/10.1371/journal.pbio.300093


Provided by PLOS

NUS Researchers Discover Protein That Promotes Chemotherapy Resistance (Medicine)

Chemotherapy is a drug treatment that uses powerful chemicals to kill fast-growing cancer cells in the body. It is a systemic treatment where drugs travel throughout the body and destroy cancer cells that have spread (metastasized) to parts of the body far away from the original (primary) tumour. As such, chemotherapy remains the main treatment against various cancers. Thus, when cancer cells resist chemotherapeutic drugs, treatment failure results.

The resistance of cancer cells to chemotherapy is marked by changes and increased output of certain proteins. These altered proteins can help doctors to identify patients who will not respond well to chemotherapy and paves the way for the development of therapeutic intervention to “re-sensitise” their cancer cells to treatment.

In a Nature Communications article published mid-April, Associate Professor Zhang Yongliang from NUS Yong Loo Lin School of Medicine’s Immunology Translational Research Programme reported the finding of one such altered protein in a study that identified how a molecule called DUSP16 plays an important role in a cancer patient’s response to chemotherapeutic drugs.

Assoc Prof Zhang and his study team, in collaboration with clinical scientists including the team led by Professor Goh Boon Cher, Deputy Director of both the Cancer Science Institute of Singapore at NUS and NUS Center for Cancer Research (N2CR), found that an increased expression of DUSP16 led to resistance from cancer cells to chemotherapy in colorectal, nasopharyngeal, gastric and breast cancer. Prof Goh’s team studies mainly cancers of the upper aerodigestive tracts (of the head and neck and lung), which are among the most frequent cancers, and seeks to understand these diseases.

These four cancers are among the most common and deadly ones affecting Singaporeans and Southeast Asians. Nasopharyngeal cancer has a high incidence rate in Southeast Asians, while colorectal cancer is the most frequently occurring cancer in Singapore. Breast cancer is the cancer with the highest incidence among women in Singapore and gastric cancer is among the top three cancers causing death worldwide. In addition, the fact that these four cancers manifest as solid tumours with chemotherapy being a common form of post-operative treatment meant that they made for good candidates for the study.

Analysis of head and neck cancer patients, and breast cancer patients showed that those with higher DUSP16 expression in their cancer cells lived for significantly shorter periods compared to patients with lower levels of DUSP16. DUSP16 expression can thus be used as a biomarker for sensitivity of cancer patients to chemotherapy, which will be important for clinicians seeking to design suitable treatment, said Assoc Prof Zhang. This molecule could also be targeted for the development of new therapies to improve the success of chemotherapy treatment. While this discovery is not only relevant to these four types of cancer, more research would be needed to examine other cancer types.

The study also found that chemotherapy drugs are a factor in the increased expression of DUSP16. This means that once chemotherapy begins, the expression of DUSP16 will increase in patients, Assoc Prof Zhang added. In addition, other factors such as stress or infections have also caused increased expression of DUSP16.

While there are no alternative treatments that might be effective in cancer patients who test positive for the increased expression of DUSP16, Assoc Prof Zhang and his team are planning to conduct further research to identify molecules and drugs that can reduce DUSP16 levels in patients.

The NUS Medicine Immunology Translational Research Programme aims to understand the role of the immune system in health and diseases. The programme strives to enable the discovery and development of more effective immunotherapy, new treatment guidelines and diagnostic tests for patients with disease-specific problems such as autoimmune and airway diseases, cancer, chronic inflammation, infections and organ/ tissue transplantation. These goals are to be achieved by fostering collaborative research and advancing latest technologies to probe immunological mechanisms, and enhancing infrastructure for clinical translation.

Featured image: DUSP16 protein expression level is associated with cancer cell sensitivity to cisplatin. © Low et al.


Reference: Low, H.B., Wong, Z.L., Wu, B. et al. DUSP16 promotes cancer chemoresistance through regulation of mitochondria-mediated cell death. Nat Commun 12, 2284 (2021). https://doi.org/10.1038/s41467-021-22638-7


Provided by National University of Singapore

Breakthrough in the Understanding of a Protein With a Key Role in Cancer (Medicine)

The neutron reflexometry method has given scientists an atomic-level insight into the behaviour of Bcl-2, a protein that promotes cancerous cell growth. The new study was carried out by Umeå chemists in collaboration with the research facilities ESS and ISIS and is published in Nature Communications Biology.

Elevated function of the cell-protecting membrane protein Bcl-2 can promote cancer and cause resistance to cancer treatment. Developing an understanding of the way it does this could inform the development of anti-cancer drugs.  

It may seem counter-intuitive, but cell death is crucial to overall health, and is managed by a series of proteins from the Bcl-2 family. These proteins work together at the membrane surface of intracellular organelles – the mitochondria – to determine a cell’s wellbeing. However, overproduction of the cell-protecting Bcl-2 members can interrupt this delicate balance and inhibit signals for cell death. This can cause cancerous cells to continue to grow, and not respond to cancer treatment.

However, how cell-protecting and cell-killing proteins of the Bcl-2 family interact with one another in their intracellular membrane environment is not fully understood, since a picture of their structure and behaviour in this environment was not available.

placeringen och beteendet för Bcl-2-proteinet
Schematic representation of two complementary biophysical approaches to elucidate structural and positional information for proteins in their membrane environment. Image: Gerhard Gröbner

In this study, the researchers used the novel combination of neutron reflectometry (NR) and NMR spectroscopy to study full-length human Bcl-2 protein located in its unique membrane environment, providing insight into the key structural and dynamic features.

Also partner in the research collaboration is European Spallation Source (ESS), an international Big Science facility currently under construction in Lund, Sweden, that will use neutrons for materials research within e.g. structural chemistry. Dr Hanna Wacklin-Knecht, ESS and Physical chemistry Division at Lund University, has contributed with expertise to optimize samples and experiment conditions as well as providing the deuterated lipids for the follow-up studies on the function of Bcl-2s that have been conducted later.

”The project with Professor Gröbner is an excellent example of how close collaboration with the research facilities ESS and ISIS helps new research groups to use neutrons in their pioneering research and prepares them to become early users of ESS. The collaboration was made possible thanks to the Swedish Research Council’s specially targeted project grants to promote neutron research in Sweden,” says Hanna Wacklin-Knecht, ESS Life Scientist.

The NR experiments were performed in collaboration with Dr Luke Clifton at the ISIS Neutron and Muon Source research facility in Oxfordshire, England on one of the leading instruments in the world for this type of experiment. These studies made it possible for the Umeå researchers to determine the relative distribution of Bcl-2 protein across the membrane. The results showed that the protein is in the membrane rather than on the surface, as previously thought.

Gerhard Gröbner, kemi
Gerhard Gröbner, Professor at the Department of Chemistry at Umeå University. Image: Tobias Sparrman

The NMR experiments looked at individual protein segments and their behaviour in the membrane, and suggest that the part of the protein that acts as a molecular switch is on, or close to, the membrane interface. However, the main protein body that blocks cell-killing partners is restricted  within the membrane. The researchers’ results have led to a significant breakthrough in the understanding of how Bcl-2 exerts its cell-protective function at the membrane level by simply inhibiting cell-killing proteins there.

“We have discovered the location and behaviour of the Bcl-2 protein in its native membrane. It is a breakthrough, not only in understanding the molecular cell-protecting function of Bcl-2, but also its notorious role in cancers, thereby making this protein a prime target in the hunt for novel cancer therapies,” says Professor Gerhard Gröbner, Department of Chemistry at Umeå University.

In future experimental studies, Gerhard Gröbner hopes to discover how the position of Bcl-2 in the membrane is related to the way that it prompts cell death.

 “Together, we now plan to unravel the active state of Bcl-2 protein when caught in the act of binding cell-killing proteins at the membrane.”

Featured image: Professor Gerhard Gröbner and research engineer Jörgen Åden are changing a sample at SURF, a neutron reflectometer at ISIS, a national research structure at Harwell in England. Image: Tobias Sparrman


About the scientific publication

A. U. Mushtaq, J. Ådén , L. A. Clifton , H. Wacklin-Knecht , M. Campana , A. P. G. Dingeldein, C. Persson, T. Sparrman, and G. Gröbner: Neutron reflectometry and NMR spectroscopy of full length Bcl-2 protein reveal its membrane localization and conformation. Nature Communications Biology 4, 507 (2021). https://doi.org/10.1038/s42003-021-02032-1


Provided by UMEA University

Freeze! Executioner Protein Caught in the Act (Biology)

A new molecular ‘freeze frame’ technique has allowed WEHI researchers to see key steps in how the protein MLKL kills cells.

Small proteins called ‘monobodies’ were used to freeze MLKL at different stages as it moved from a dormant to an activated state, a key process that enables an inflammatory form of cell death called necroptosis. The team were able to map how the three-dimensional structure of MLKL changed, revealing potential target sites that might be targets for drugs – a potential new approach to blocking necroptosis as a treatment for inflammatory diseases.

The research, which was published in Nature Communications, was led by Associate Professor James Murphy and PhD students Ms Sarah Garnish and Mr Yanxiang Meng, in collaboration with Assistant Professor Akiko Koide and Professor Shohei Koide from New York University, US.

At a glance

  • The ‘executioner’ protein MLKL kills cells through an inflammatory process called necroptosis.
  • Monobody technology has enabled WEHI researchers to capture different forms of MLKL as it becomes activated and moves to kill the cell.
  • Understanding how the three-dimensional shape of MLKL changes may lead to the development of drugs that prevent necroptosis, as a treatment for inflammatory diseases.

Key steps in necroptosis

MLKL is a key protein in necroptosis, being the ‘executioner’ that kills cells by making irreparable holes in their exterior cell membrane. This allows the cell contents to leak out and triggers inflammation – alerting nearby cells to a threat, such as an infection.

Ms Garnish said MLKL was activated within a protein complex called a ‘necrosome’ which responded to external signals.

A cell in yellow is shown dying by necroptosis, a process requiring the protein MLKL © WEHI Australia

“While we know which proteins activate MLKL, and that this involves protein phosphorylation, nobody had been able to observe any detail about how this changes MLKL at the structural level. It happens so fast that it’s essentially a ‘molecular blur’,” she said.

A new technology – monobodies – developed by Professor Koide’s team, was key to revealing how MLKL changed.

Monobodies that specifically bound to different ‘shapes’ of MLKL were used to capture these within cells, Mr Meng said.

“These monobodies prevented MLKL from moving out of these shapes – so we could freeze MLKL into its different shapes,” he said.

“We then used structural biology to generate three-dimensional maps of these shapes which could be compared. This revealed that MLKL passed through distinct shape changes as it transitioned from being activated through to breaking the cell membrane.”

An important step

Associate Professor Murphy said the structures provided the first formal evidence for how MLKL changed its shape after it was activated.

“Until now, we’ve speculated that this happens, but it was only with monobodies that we could actually prove there are distinct steps in MLKL activation,” he said.

“Necroptosis is an important contributor to inflammatory conditions such as inflammatory bowel disease. There is intense interest in MLKL as a key regulator of necroptosis – and how it could be blocked by drugs as a potential new anti-inflammatory therapy.”

The research was supported by the Australian Government National Health and Medical Research Council and Department of Education, Skills and Employment, a Melbourne Research Scholarship, the Wendy Dowsett Scholarship, an Australian Institute of Nuclear Science and Engineering Postgraduate Research Award, the Australian Cancer Research Foundation, the US National Institutes of Health and the Victorian Government.

The Australian Synchrotron’s MX beamlines were critical infrastructure for the project.

WEHI authors: Ms Sarah Garnish, Mr Yanxiang Meng, Dr Jarrod Sandow, Ms Annette Jacobsen, Dr Andre Samson, Dr Christopher Horne, Dr Cheree Fitzgibbon, Mr Samuel Young, Ms Phoebe Smith, Associate Professor Andrew Webb, Dr Emma Petrie, Dr Joanne M. Hildebrand, Associate Professor Peter Czabotar, Associate Professor James Murphy

Featured image: PhD students Mr Yanxiang Meng (L) and Ms Sarah
Garnish (R) have discovered a key step in how the protein MLKL kills cells


Reference: Garnish, S.E., Meng, Y., Koide, A. et al. Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis. Nat Commun 12, 2211 (2021). https://doi.org/10.1038/s41467-021-22400-z


Provided by WEHI

Protein Based Biomarker Identifies the Chemo Drug Sensitivity (Medicine)

Cancer is the world’s second deadliest disease which contributes towards the fatality of over 10 million people per year. Oncologists adopt a variety of treatment procedures to treat cancer cells. Among the different methods used to fight cancer, chemotherapeutic treatment is a prominent and well-adopted technique. It is a drug based method, wherein powerful chemical compounds are injected into the body to annihilate the malignant cells. Although these chemicals support the destruction of the cancerous cells, optimizing their dosage has always been a challenge to the medical specialists.

Cisplatin is a chemotherapy medication which is used to treat a number of cancers such as lung cancer, brain tumor, breast cancer, liver cancer etc. This platinum-metal based chemotherapy drug is highly powerful and is instituted by the intravenous route into the body. Although it is renowned for effective destruction of cancerous cells for the past 4 decades, its alarming side effects is of serious concern to the medical community. Researchers have reported that administration of high dosage of the chemical is not only ineffective on the tumor cells but is also responsible for adverse side effects which may even lead to the sudden demise of the patient. control on the level of the cisplatin drug has been a matter of persisting concern for medical practitioners.  A recent study on monitoring the cisplatin level in liver cancer cells reported by researchers from the Graduate School of Medical and Dental Sciences at Niigata University and their collaborators from Niigata Medical Center, Uonuma Institute of Community Medicine Niigata University Hospital, Niigata City General Hospital, Saiseikai Niigata Hospital and, Kashiwazaki General Hospital and Medical Center provides a ray of hope to the health professionals. The findings were published recently in the prestigious Scientific Reports journal from Nature publishing house. The multi-disciplinary research team has identified adipose most abundant 2 protein (APM2) as a potential marker to indicate the permissible level of the drug. They have experimentally investigated the liver and gastro cancer cells and have compared the variation in the protein concentration in the presence and absence of the chemo drug.

Over expression of APM2 induce resistance to cisplatin © Nigata University

“Our results demonstrate a significant relationship between the high level of APM2 expression in serum, cancerous cells in the liver, the surrounding liver tissue and cisplatin resistance. The study reveals that APM2 expression is related to cisplatin sensitivity” explains Professor Kenya Kamimura of the Division of Gastroenterology and Hepatology, the Graduate School of Medical and Dental Sciences, Niigata University. The research study paves way for effective monitoring of chemotherapeutic drug level and their safe administration. Professor Kenya Kamimura states with confidence that, “The serum APM2 can be an effective biomarker of the liver and gastric cancer cells for determining the sensitivity to cisplatin.  The results of the study would provide an advantage for the technicians, allowing easy adaption in small local clinics.”

The research group has noticed that APM2 concentration favours the development of ERCC6L gene card. This is manifested by the growth of the cancerous cells and marks the resistance to the chemo drug.  The valuable findings offers the potential to control the cisplatin dosage level and avoid cytotoxicity. Such a study is essential in today’s context as research groups across the globe strive to develop new methodologies to optimize the dosage and control the severe side-effects induced by the concentration of chemo drugs. The research team has also utilized bioinformatics based tools to complement the experimentally obtained results.

Serum APM2 concentration could estimate the cisplatin sensitivity of the liver cancer © Nigata University

“To the best of our knowledge, this is the first report to demonstrate that the serum level of APM2 can be the predictor of the CDDP chemosensitivity. This study thus represents a milestone for detecting CDDP sensitivity, and further studies will help modify APM2 expression, which could contribute to the chemosensitization of the tumor” describes Professor Kenya Kamimura.

The interesting results of the research study has laid a foundation to track the chemo drug level. Future studies will explore the mechanism and relation between APM2 and ERCC6L. Such studies are on the cutting edge research areas of oncological sciences and hold immense potential in further extending the results to other types of cancers.

The research in the authors’ laboratories has been supported in part by a Grant-in-Aid for Scientific Research from the Japanese Society for the Promotion of Sciences 20390205, 25670370, and 23659395 to Takeshi Suda and Yutaka Aoyagi; 17K09408 to Kenya Kamimura; and grant provided from the Ichiro Kanehara Foundation.

Featured image: APM2 overexpression increases ERCC6L expression © Nigata University


Publication Details

Journal: Scientific Reports
Title: Adipose Most Abundant 2 Protein is a Predictive Marker for Cisplatin Sensitivity in Cancers
Authors: Kenya Kamimura, Takeshi Suda, Yasuo Fukuhara, Shujiro Okuda, Yu Watanabe, Takeshi Yokoo, Akihiko Osaki, Nobuo Waguri, Toru Ishikawa, Toshihiro Sato, Yutaka Aoyagi, Masaaki Takamura, Toshifumi Wakai & Shuji Terai
DOI: 10.1038/s41598-021-85498-7


Provided by Nigata University

Dynamic Model of SARS-CoV-2 Spike Protein Reveals Potential New Vaccine Targets (Biology)

New model captures glycan molecules whose motions shield much of the spike from immune defenses

A new, detailed model of the surface of the SARS-CoV-2 spike protein reveals previously unknown vulnerabilities that could inform development of vaccines. Mateusz Sikora of the Max Planck Institute of Biophysics in Frankfurt, Germany, and colleagues present these findings in the open-access journal PLOS Computational Biology.

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. A key feature of SARS-CoV-2 is its spike protein, which extends from its surface and enables it to target and infect human cells. Extensive research has resulted in detailed static models of the spike protein, but these models do not capture the flexibility of the spike protein itself nor the movements of protective glycans–chains of sugar molecules–that coat it.

To support vaccine development, Sikora and colleagues aimed to identify novel potential target sites on the surface of the spike protein. To do so, they developed molecular dynamics simulations that capture the complete structure of the spike protein and its motions in a realistic environment.

These simulations show that glycans on the spike protein act as a dynamic shield that helps the virus evade the human immune system. Similar to car windshield wipers, the glycans cover nearly the entire spike surface by flopping back and forth, even though their coverage is minimal at any given instant.

By combining the dynamic spike protein simulations with bioinformatic analysis, the researchers identified spots on the surface of the spike proteins that are least protected by the glycan shields. Some of the detected sites have been identified in previous research, but some are novel. The vulnerability of many of these novel sites was confirmed by other research groups in subsequent lab experiments.

“We are in a phase of the pandemic driven by the emergence of new variants of SARS-CoV-2, with mutations concentrated in particular in the spike protein,” Sikora says. “Our approach can support the design of vaccines and therapeutic antibodies, especially when established methods struggle.”

The method developed for this study could also be applied to identify potential vulnerabilities of other viral proteins.

In your coverage please use this URL to provide access to the freely available article in PLOS Computational Biologyhttps://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1008790

Funding: This work was supported by the Max Planck Society (https://www.mpg.de) (GH), the Austrian Science Fund FWF Schrödinger Fellowship J4332-B28 (https://www.fwf.ac.at) (MS), the Human Frontier Science Program RGP0026/2017 (https://www.hfsp.org) (GH), the Landes-Offensive zur Entwicklung Wissenschaftlich-Ökonomischer Exzellenz LOEWE of the State of Hesse (https://wissenschaft.hessen.de/wissenschaft/landesprogramm-loewe): DynaMem (GH) and CMMS (RC and GH), the Frankfurt Institute for Advanced Studies (https://fias.institute): (RC), and the Leibniz Supercomputing Centre Munich (https://www.lrz.de): SUPERspike (GH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Featured image: In this visualization of antibody target sites, the SARS-CoV-2 spike protein is tethered to the viral membrane with a slender stalk. Patches of intense purple color at the surface of spike indicate potential target sites for antibodies that are not protected by the glycans –chains of sugar molecules–shown in green. These binding sites and their accessibility were identified with molecular dynamics simulations that capture the complete structure of the spike protein and its motions in a realistic environment. © Mateusz Sikora, Sören von Bülow, Florian E. C. Blanc, Michael Gecht, Roberto Covino and Gerhard Hummer


Reference: Sikora M, von Bülow S, Blanc FEC, Gecht M, Covino R, Hummer G (2021) Computational epitope map of SARS-CoV-2 spike protein. PLoS Comput Biol 17(4): e1008790. https://doi.org/10.1371/journal.pcbi.1008790


Provided by PLoS

U of A Team Identifies Protein That Blocks Body’s Ability to Clear Bad Cholesterol (Medicine)

Researchers are now looking to develop a drug that will boost existing statin drugs to prevent heart disease.

A team of researchers at the University of Alberta has uncovered a long-sought link in the battle to control cholesterol and heart disease.

The protein that interferes with low-density lipoprotein (LDL) receptors that clear “bad” cholesterol from the blood was identified in findings recently published in Nature Communications by Dawei Zhang, associate professor of pediatrics in the Faculty of Medicine & Dentistry. Excess LDL cholesterol can lead to atherosclerosis—a narrowing and hardening of arteries—and ultimately, heart attack.

“We have known for many years that these receptors could be cleaved, but nobody knew which protein was responsible,” said Zhang. “There had been several attempts around the world but nobody else was successful.”

Now that the culprit has been identified, Zhang’s lab is already at work to find a drug to target the protein, allowing the receptors to clear more LDL. 

A cholesterol-reducing class of drugs called statins—Lipitor and Crestor are two well-known brand names—has been shown to reduce cardiac events by 20 to 40 per cent, but they have side-effects that mean they can’t be given in high enough doses to work for everyone. The new drug would be used in combination with statins to boost their effect, Zhang said.

A serendipitous discovery 

Zhang’s team stumbled upon the role of the protein—membrane type 1 matrix metalloproteinase—by accident while studying another protein involved in heart function. They then set out to repeat and confirm their findings in mouse, rat and human cells, working in collaboration with researchers in China and other faculty members at the U of A. Their study was funded by the Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research. Zhang is also a member of the Women and Children’s Health Research Institute.

The protein has other critical physiological functions, Zhang explained, so his lab will work to identify and focus on the specific region within the protein that acts on the LDL receptor. They are also working with a new technique to further target their potential drug so it will work only within the liver, further reducing the likelihood of unwanted side-effects. Their early results are encouraging, Zhang said.

Zhang noted the protein is also critical for cancer tumour invasion, so the team will collaborate with U of A oncology experts to learn more.

“The one protein is a shared risk factor for the two most common diseases in humans—cancer and cardiovascular disease,” he said. “We will explore whether we can target one protein to reduce the incidence of the two most common human diseases.”

Featured image: U of A researcher Dawei Zhang was part of an international team that identified the protein that interferes with the body’s ability to get rid of “bad” cholesterol, which could point the way to better treatments to prevent heart disease. (Photo: Faculty of Medicine & Dentistry)


Reference: Alabi, A., Xia, XD., Gu, HM. et al. Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis. Nat Commun 12, 1889 (2021). https://doi.org/10.1038/s41467-021-22167-3


Provided by University of Alberta