ScienceDaily (Nov. 29, 2012) ? Scientists at The Scripps Research Institute (TSRI) have determined how two proteins help create organelles, or specialized subunits within a cell, that play a vital role in maintaining cell health. This discovery opens the door for research on substances that could interfere with the formation of these organelles and lead to new therapies for cancer.
The study, published online ahead of print on December 2, 2012, by the journal Nature Structural & Molecular Biology, focuses on the structure and function of the two proteins, ATG12 and ATG5. These proteins need to bond correctly to form an organelle called the autophagosome, which acts like a trash bag that removes toxic materials and provides the cell with nutrition through recycling.
"Our study focuses on one of the big mysteries in our field," said Takanori Otomo, the TSRI scientist who led the effort. "These proteins are linked, but no one has explained why clearly. We're very excited to have determined the structure of these linked proteins so that the information is available to do the next level of research."
Asking Questions, Finding Answers
At the beginning of the study, Otomo and colleagues knew that many proteins work together to form autophagosomes as part of the process known as autophagy, which breaks down large proteins, invasive pathogens, cell waste, and toxic materials. As part of this process, one key protein, LC3, attaches to a lipid, or fat molecule, on the autophagosome membrane. Yet LC3 cannot attach to a lipid without the help of ATG12 and ATG5, and a cell will only form an autophagosome if the linkage, or conjugate, between these two molecules has been established.
Otomo and colleagues set out to determine the shape of the ATG12-ATG5 conjugate, and to find out why it was needed for LC3 lipidation.
Using a method called X-ray crystallography, the scientists were able to unveil the details of this conjugate. When ATG12 and ATG5 come together, they form a rigid architecture and create a surface area that is made up of evolutionarily conserved amino acids and facilitates LC3 lipidation. The researchers confirmed this finding by mutating those conserved amino acids , which prevented an autophagosome from forming.
Otomo and colleagues also identified a surface on the ATG12-ATG5 conjugate that binds to ATG3, another enzyme required to attach LC3 to the lipid.
Toward Better Understanding and New Cancer Treatments
With this new knowledge, the researchers hope to design molecules that inhibit autophagosome formation, a direction of research that has implications for cancer treatment. A drug that directly inhibits ATG3 binding, for example, could be used in coordination with current therapies to make cancer treatments more effective, preventing a cancer cell from recycling nutrients and prolonging its survival.
"Ultimately, we'd like to understand the molecular mechanisms of each step of autophagy," he said, "As we make progress toward this goal, we will have a better idea of how to manipulate the pathway for therapeutic purposes. This field is still young and there are a lot of unknowns. This work is just the beginning."
This research was supported by National Institutes of Health (NIH) grant GM092740 and by funds from Japan Science and Technology Agency through the Keio Kanrinmaru Project.
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The above story is reprinted from materials provided by The Scripps Research Institute.
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Journal Reference:
- Chinatsu Otomo, Zoltan Metlagel, Giichi Takaesu, Takanori Otomo. Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy. Nature Structural & Molecular Biology, 2012; DOI: 10.1038/nsmb.2431
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Source: http://feeds.sciencedaily.com/~r/sciencedaily/top_news/top_health/~3/efU9jJ_Od0I/121202164103.htm
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Apple released its newest version of iTunes yesterday, and it's a complete overhaul to the entire program. As you'd expect, that means there's a few cool (somewhat) hidden features. Here are a few we've found especially helpful. 
Let's start with what we're guessing is most people's main gripe: it looks different. It's true, it does, and if you're not a fan of browsing your music library with giant covers, and navigating drop-down menus, iTunes 11 is a bit annoying. The good news? You can get the old look back:
Entering in the code from a gift certificate is always a bit annoying. With iTunes 11, all you need is a camera:
Cover Flow is gone in iTunes 11 and it's replaced with the new "Expanded View." When you're viewing your library by Albums, simply select an album, and you get an expanded view right there with all the album info. It works a lot better than Cover Flow and makes it so you can quickly view album info without leaving the place you're at. You can either click the album art again, or the "X" in the right corner to make it go away.
Ever have those moments where you're listening to a song and it reminds you of another song? You don't want to stop the song playing, but you do want to cue up the song you're thinking of. That's what "Up Next" lets you do. Instead of creating playlists for everything, you can create on-the-fly playlists of songs or albums.
If you use a bunch of Apple products, say, an iPhone, iPad, and iPod Touch, one of the best new features in iTunes 11 is that it saves your progress in your media across all devices through iCloud. So, if you pause a movie, TV show, podcast, audiobook, or iTunes U file on your desktop, you can pick up right where you left off on another device.
In older versions of iTunes, the MiniPlayer didn't do much except allow you to pause or skip tracks. Now, MiniPlayer allows you to search for new tracks, add new songs to the "Up Next" queue, and even control AirPlay volume.
The iTunes Store now tracks everything you listen to in its preview history panel. When you're in the store, click the list icon in the top right corner, and you're shown all the stuff you listened to recently. You can hit "Clear" to get rid of everything in the list Also worth noting is that provided you're signed in with iCloud, your previewed tracks on all your devices will sync here. So, if you preview a song on your iPhone, it will show in your preview history in iTunes.
This isn't the most earth-shattering of news, but in iTunes 11 you have two main search areas: the store and your library. That's it. In previous versions you had to search separately for video, music, or podcasts. Now, it searches your entire local library, or the iTunes store for everything.
One of the most annoying things to do in older versions of iTunes was trimming down the apps downloaded on your computer. You had to do it in the Apps panel with large icons that seemed to take forever to load. Now you can do it with in a List View, and it supports the same basic sort options you get with music (Date Added, Purchase Date, Size, etc).