Importin-9 wraps around the H2A-H2B core to act as nuclear importer and histone chaperone

Cells contain two meters of DNA which, if left to its own devices, would soon end up in a knot. To keep things organized, the genetic code is wrapped around protein ‘spools’ called histones, meaning it can all fit within a part of the cell known as the nucleus. The cell makes a copy of its DNA every time it divides, and this copy needs a new set of histones to keep it tidy. The machinery required to construct new histones sits outside the nucleus and getting the histones into position in the nucleus can be a challenge. Histones have a positive charge, which helps to keep the negatively charged DNA wound around the spool. Yet without supervision, histones can stick to other charged molecules in the cell and cause blockages. The proteins responsible for histone transport are called importins. These proteins normally recognize their cargo by molecular patterns called “nuclear localization signals”. These patterns work like a postal address, telling the importin to take the cargo into the nucleus. When they arrive at their destination, another protein called Ran interacts with the importins to release the cargo. Strangely, removing the predicted address pattern from histones does not stop them getting to the nucleus. To find out what was going on, Padavannil et al. solved the three-dimensional structure of an importin bound to a pair of histones via a technique called X-ray crystallography. This made it possible to see how the proteins fit together. The structure revealed that, rather than interact with the predicted address pattern, the importin wraps around the core of the histones. This blocks the positive charges, stopping the histones sticking to other molecules on their way to the nucleus. The next challenge was to find out how the cell unhooks the histone cargo from the importin when it arrives in the nucleus; with the positive charges covered by the importin, the histones could not stick to the DNA. Yet, something changed when the levels of Ran were high. Rather than unhook the histone, Ran joined the importin-histone complex. This then made it possible for the histones to attach to DNA, helping them to get into position without sticking to the wrong molecules. These findings form the first step in understanding how the cell transports sticky histones without getting in a knot. The next step is to find out whether these interactions, shown in test tubes, happen in the same way inside living cells.