The Hsp90 molecular chaperone and its Cdc37 cochaperone help stabilize and activate more than half of the human kinome. However, both the mechanism by which these chaperones assist their "client" kinases and the reason why some kinases are addicted to Hsp90 while closely related family members are independent are unknown. Our structural understanding of these interactions is lacking, as no full-length structures of human Hsp90, Cdc37, or either of these proteins with a kinase have been elucidated. Here we report a 3.9 angstrom cryo–electron microscopy structure of the Hsp90-Cdc37-Cdk4 kinase complex. Surprisingly, the two lobes of Cdk4 are completely separated with the?4-?5 sheet unfolded.
Although some proteins can reach a properly folded state without assistance, many require help to adopt the correct topology and avoid kinetic trapping in nonnative states. Chaperones encapsulate guest proteins and use adenosine triphosphate (ATP)–driven conformational changes to help them fold, but not all chaperones work for all substrates. Balchin et al. compared the folding pathway of the cytoskeleton protein actin with its proper chaperone, TRiC, to the incorrect folding that occurs with the bacterial chaperone GroEL. TRiC functions by stabilizing an extended form of actin with the proper secondary structure and topology. ATP binding and hydrolysis drives release of this partially folded intermediate into the chaperone where it can successfully fold.
Normally when you're tooling around in a virtual world, you want the experience to be as immersive as possible. But there's a downside to being cut off from the outside world -- what if the phone rings or the pizza guy starts knocking or a crazed ax murderer breaks in the back door? Well, if you happen to have a pair of JBL Everest Elite headphones and an HTC Vive, you'll be able to take that call, receive that pizza or head Mr. Choppy off at the stairs. The system works by pairing the JBL's Ambient Aware feature to the Vive's Chaperone boundary markers. Basically, when you hit the edge of the Vive activity zone, right when those Chaperone wireframe boundary markers pop up, the JBLs will lower the in-game audio and turn on the headphone's external mics so that you can hear what's going on around you.
Over the past decade, we have gained substantial new insight into the overall behavior of the PN and the molecular mechanics of its components. Advances in structural biology and biophysical approaches have allowed chaperone mechanisms to be interrogated at an unprecedented level of detail. Recent work has provided fascinating insight into the process of protein folding on the ribosome and revealed how highly allosteric chaperones such as the heat shock protein 70 (Hsp70), Hsp90, and chaperonin systems modulate the folding energy landscapes of their protein clients. Studies of chaperone systems from bacteria and eukaryotes have revealed common principles underlying the organization of chaperone networks in different domains of life. Recently, we have begun to appreciate the relative complexity of eukaryotic chaperones and are starting to understand how eukaryotes deal with the challenge of folding a large proteome enriched in multidomain proteins.