Hexbyte Glen Cove Class II PI3K lipid kinase: Structure of novel antithrombotic drug target resolved

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Structural model of active PI3KC2 at the plasma membrane. In this open conformation the distal PX and C2 domains associate with plasma membrane lipids, while the Ras-binding domain (RBD) binds to a so far unknown Rab protein. Credit: Wen-Ting Lo, FMP

Phosphatidylinositol 3-kinase, or PI3K for short, is a family of lipid kinases that plays a key role in the human body, performing functions such as cell division, metabolism, and cell growth.

While class I PI3Kα is well-researched and an important target for cancer drugs, little is known about class II of this lipid kinase family. Now, researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) have been able to shed light on its structure and function. The results pave the way for the development of new types of antithrombotic drugs. Moreover, it is likely that the inhibition of class II PI3KC2α is able to arrest tumor angiogenesis. The study has now been published in Nature Structural & Molecular Biology. A second paper published in Science provides another important lead.

Lipid kinases are among the promising targets of new classes of drugs, due mainly to class I PI3Kα, which plays a crucial role in and . This enzyme is hyperactive in 30-40% of all tumors, leading to uncontrolled cell growth. For this reason, this well-researched lipid kinase has become a prime target for the development of anticancer drugs for the past two decades.

In contrast, little is known about its sister enzyme, class II PI3Kα. It is thought that this lipid kinase is likewise associated with numerous biomedical processes such as platelet aggregation or the formation of new blood vessels, referred to as angiogenesis. However, before its dysfunction can be better understood and targeted by drugs, it is essential to know exactly what this kinase looks like and how it functions.

This is precisely what researchers from FMP have now managed to achieve. Using a combination of X-ray protein crystallography and cryo-electron microscopy (cryo-EM), Professor Volker Haucke’s research group has succeeded in resolving the structure of class II PI3Kα (PI3KC2α) and in describing the activation mechanism of the enzyme for the first time. These findings pave the way for entirely novel therapeutic approaches.

Inhibition of kinase activity could help numerous patients

“Inhibition of kinase activity is thought to play a role in many applications in biomedicine, such as tumor growth and angiogenesis,” explained Volker Haucke. “It is also likely to be important for the inhibition of platelet aggregation.”

It is known, for example, that the kinase is required for platelets to form a thrombus. It is interesting to note that the function of kinase PI3KC2α is flow-dependent, i.e. it depends on blood pressure. If a were now used to inhibit the kinase, platelet aggregation would be arrested, especially in the case of an increase in blood pressure. However, most anticoagulants currently prescribed to patients to prevent thromboembolic events such as heart attack or stroke are also effective at normal blood pressure levels, which can have fatal side effects such as brain hemorrhage. The FMP researchers conjecture that PI3KC2α kinase inhibitors would have a significantly better pharmacological and biomedical profile than existing antiplatelet drugs.

Initial experiments with potential drug candidates have already demonstrated that inhibition of the kinase is possible in principle. Unraveling the structure and activation mechanism was key to this.

Conditions created for new drugs

The researchers have in fact discovered the structure of the binding pocket of the kinase that binds the lipid and adenosine triphosphate (ATP) as the “cellular currency,” enabling the transfer of a phosphate group to the lipid. The scientists now also know what kind of “molecular gymnastics” the kinase must undergo in order to be activated at exactly the right place in the cell.

“This information is crucial for developing a specific inhibitor that blocks only PI3KC2a, but no other related enzyme,” stated Wen-Ting Lo, the first author of the study. The team around Volker Haucke and Wen-Ting Lo is already collaborating with other scientists at the institute to find specific inhibitors that occupy the ATP-binding pocket of the enzyme, preventing the enzymatic reaction.

Kinase involved in the final step of cell division

But this is not all that FMP researchers have found out about PI3KC2a. Together with Emilio Hirsch’s research group at the University of Torino, the researchers have been able to demonstrate that the kinase is also involved in the final step of cell division, referred to as cytokinesis.

Patients lacking the kinase due to mutations were the starting point of the study published in Science. Besides having various organ defects, these individuals suffer from a clouding of the lens, known as a cataract. Using experiments in mice and zebrafish, the research team was able to show how the loss of function of the leads to cataracts.

The genetic material is duplicated and subsequently distributed to the two daughter during cell division. Membrane abscission eventually separates the daughter cells. In the absence of the kinase, however, this final cut fails to occur because a crucial lipid that can only be produced by PI3KC2a is missing. As a result, the lens epithelial cells suffer from impaired cytokinesis, which explains why these patients develop cataracts. The finding also has further implications: With the realization that the kinase is an essential component of cytokinesis, i.e. the separation of daughter cells—this mechanism could also be of great importance for tumors that rely on continuous cell division. Consequently, PI3KC2a inhibitors would potentially also open up new perspectives in cancer therapy.

More information:
Wen-Ting Lo et al, Structural basis of phosphatidylinositol 3-kinase C2α function, Nature Structural & Molecular Biology (2022). DOI: 10.1038/s41594-022-00730-w

Federico Gulluni et al, PI(3,4)P2-mediated cytokinetic abscission prevents early senescence and cataract formation, Science (2021). DOI: 10.1126/science.abk0410


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Hexbyte Glen Cove New class of habitable exoplanets represent a big step forward in the search for life thumbnail

Hexbyte Glen Cove New class of habitable exoplanets represent a big step forward in the search for life

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Astronomers have identified a new class of habitable planets, dubbed ‘Hycean’ planets – hot, ocean-covered planets with hydrogen-rich atmospheres – which could represent a big step forward in the search for life elsewhere. Credit: Amanda Smith, University of Cambridge

A new class of exoplanet very different to our own, but which could support life, has been identified by astronomers, which could greatly accelerate the search for life outside our Solar System.

In the search for life elsewhere, astronomers have mostly looked for planets of a similar size, mass, temperature and atmospheric composition to Earth. However, astronomers from the University of Cambridge believe there are more promising possibilities out there.

The researchers have identified a new class of habitable planets, dubbed ‘Hycean’ planets—hot, ocean-covered planets with hydrogen-rich atmospheres—which are more numerous and observable than Earth-like planets.

The researchers say the results, reported in The Astrophysical Journal, could mean that finding biosignatures of life outside our Solar System within the next two or three years is a real possibility.

“Hycean planets open a whole new avenue in our search for life elsewhere,” said Dr. Nikku Madhusudhan from Cambridge’s Institute of Astronomy, who led the research.

Many of the prime Hycean candidates identified by the researchers are bigger and hotter than Earth, but still have the characteristics to host large oceans that could support similar to that found in some of Earth’s most extreme aquatic environments.

These planets also allow for a far wider habitable zone, or ‘Goldilocks zone’, compared to Earth-like planets. This means that they could still support life even though they lie outside the range where a planet similar to Earth would need to be in order to be habitable.

Thousands of planets outside our Solar System have been discovered since the first exoplanet was identified nearly 30 years ago. The vast majority are planets between the sizes of Earth and Neptune and are often referred to as ‘super-Earths’ or ‘mini-Neptunes’: they can be predominantly rocky or ice giants with hydrogen-rich atmospheres, or something in between.

Most mini-Neptunes are over 1.6 times the size of Earth: smaller than Neptune but too big to have rocky interiors like Earth. Earlier studies of such planets have found that the pressure and temperature beneath their hydrogen-rich atmospheres would be too high to support life.

However, a recent study on the mini-Neptune K2-18b by Madhusudhan’s team found that in certain conditions these planets could support life. The result led to a detailed investigation into the full range of planetary and stellar properties for which these conditions are possible, which known exoplanets may satisfy those conditions, and whether their biosignatures may be observable.

The investigation led the researchers to identify a new class of planets, Hycean planets, with massive planet-wide oceans beneath hydrogen-rich atmospheres. Hycean planets can be up to 2.6 times larger than Earth and have atmospheric temperatures up to nearly 200 degrees Celsius, but their oceanic conditions could be similar to those conducive for microbial life in Earth’s oceans. Such planets also include tidally locked ‘dark’ Hycean worlds that may have habitable conditions only on their permanent night sides, and ‘cold’ Hycean worlds that receive little radiation from their stars.

Planets of this size dominate the known exoplanet population, although they have not been studied in nearly as much detail as super-Earths. Hycean worlds are likely quite common, meaning that the most promising places to look for life elsewhere in the Galaxy may have been hiding in plain sight.

However, size alone is not enough to confirm whether a planet is Hycean: other aspects such as mass, temperature and atmospheric properties are required for confirmation.

When trying to determine what the conditions are like on a planet many light years away, astronomers first need to determine whether the planet lies in the of its star, and then look for molecular signatures to infer the planet’s atmospheric and internal structure, which govern the surface conditions, presence of oceans and potential for life.

Astronomers also look for certain biosignatures which could indicate the possibility of life. Most often, these are oxygen, ozone, methane and nitrous oxide, which are all present on Earth. There are also a number of other biomarkers, such as methyl chloride and dimethyl sulphide, that are less abundant on Earth but can be promising indicators of life on planets with hydrogen-rich atmospheres where oxygen or ozone may not be as abundant.

“Essentially, when we’ve been looking for these various molecular signatures, we have been focusing on planets similar to Earth, which is a reasonable place to start,” said Madhusudhan. “But we think Hycean planets offer a better chance of finding several trace biosignatures.”

“It’s exciting that habitable conditions could exist on planets so different from Earth,” said co-author Anjali Piette, also from Cambridge.

Madhusudhan and his team found that a number of trace terrestrial biomarkers expected to be present in Hycean atmospheres would be readily detectable with spectroscopic observations in the near future. The larger sizes, higher temperatures and hydrogen-rich atmospheres of Hycean planets make their atmospheric signatures much more detectable than Earth-like planets.

The Cambridge team identified a sizeable sample of potential Hycean worlds which are prime candidates for detailed study with next-generation telescopes, such as the James Webb Space Telescope (JWST), which is due to be launched later this year. These all orbit red dwarf stars between 35-150 light years away: close by astronomical standards. Planned JWST observations of the most promising candidate, K2-18b, could lead to the detection of one or more biosignature molecules.

“A biosignature detection would transform our understanding of life in the universe,” said Madhusudhan. “We need to be open about where we expect to find life and what form that life could take, as nature continues to surprise us in often unimaginable ways.”

More information:
Habitability and Biosignatures of Hycean Worlds, Astrophysical Journal (2021). doi.org/10.3847/1538-4357/abfd9c

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Hexbyte Glen Cove Social class still dictates graduate job trends thumbnail

Hexbyte Glen Cove Social class still dictates graduate job trends

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Credit: CC0 Public Domain

Policies that offer sustained support are needed to ensure people from lower socio-economic groups can reap the benefits associated with a degree, researchers say. Adequate grants, mentoring on campus and tailored career advice are among the provisions that would help students make timely and smoother transitions into good graduate jobs. Making research-intensive universities more accessible to disadvantaged students would also assist the process, according to the study by the University of Edinburgh and University College London. Previous research on graduate job inequalities analyzed outcomes at just one or two points following graduation, providing only snapshots of occupational destinations.

Long-term perspective

This study examines the career trajectories of degree holders across their life and analyzes how these vary according to students’ social origins.

Data was taken from the 1970 British Cohort Study—a multi-disciplinary survey monitoring the development of babies born in the UK during the week of 5–11 April 1970. The results show that graduates originally from lower social classes have more diverse and less stable career paths than the more structured routes of their advantaged counterparts. Graduates from less privileged backgrounds are less likely to enter top-level in their 20s and more likely to enter, and remain, in lower social classes.

“Employment inequalities among graduates show that not only does the final destination matter, but also the timing and sequencing of different activities within the career paths,” says Dr. Adriana Duta.

Key factor

The relatively late age at which less advantaged students is key to some of these patterns, researchers say, as older graduates are more likely to be employed in non-graduate jobs. This finding suggests that from disadvantaged backgrounds may have improved occupational outcomes if they go to university sooner rather than later. The study found that career outcomes for better-off students were helped by the relatively high numbers—compared with disadvantaged students—who attended research-intensive universities.

Graduates from these universities are more likely to enter high professional and managerial jobs early on in their .

“There are clear social inequalities in labor market outcomes among graduates and this already uneven playing field is likely to get worse because of growing job uncertainty,” says Dr. Bozena Wielgoszewska.

Partial explanation

Educational factors—such as university attended, subjects studied and degree grade—only partly explain why disadvantaged students are more likely than their better-off peers to spend most of their working lives in non-graduate jobs. Researchers say further research is needed to uncover the other family-related factors behind this finding.

The study from the Understanding Inequalities project, funded by the Economic and Social Research Council, is published online in the journal Advances of Life Course Research.

A blog by Dr. Adriana Duta, Dr. Bozena Wielgoszewska and lead researcher Professor Cristina Iannelli, of the University of Edinburgh explores the issues further.

More information:
Different degrees of career success: Understanding inequalities in graduates’ employment pathways: www.understanding-inequalities … es-of-career-success

Social class still dictates graduate job trends (2020, November 13)
retrieved 14 November 2020
from https://phys.org/news/2020-11-social-class-dictates-job-trends.html

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