New Research: Nuclear Import of Membrane Proteins

All the cells in the body are made up of different components called organelles. For example, lysosomes recycle components of the cells, the mitochondria generate energy and the nucleus is not only stores the chemical blueprint of life (DNA), it also makes the executive decision of whether to turn genes on and off. Many of these organelles are separated from each other by barriers called membranes. Between all these organelles, proteins are being passed back and forth to different compartments through specific gates.

The nucleus has many gates called the nuclear pore complex (NPC) that regulate what can move across the nuclear membrane. Think of it as a filter; very small molecules can go through whereas large molecules normally cannot. However, the NPC has the ability to recognize a specific instruction on larger molecules called a zip-code. Think of zip-codes as a one-pass key; if a large molecule has a zip-code code for entry, it will be permitted to pass through the gate into the nucleus, but not back out unless it has the zip-code for exit.

We don't quite understand how proteins are moved across the nuclear membrane. Even more puzzling is this. The nuclear membrane actually has two-membranes bridged by the gates. There are proteins embedded in both the inner membrane and the outer membrane, yet it is not well understood how proteins are moved from the outer membrane into the inner membrane.

Anna Meinema from the Veenhoff lab explored this process for a specific inner membrane protein Heh2. She found that the transport of Heh2 into the nucleus depended on how well its zip-code could bind a protein called the karyopherin-α/β1 complex. karyopherin-α/β1 is somewhat like a parent that holds onto a kid as it crosses the street. In the nucleus, it holds onto proteins with nuclear zip-codes and carries it across the nuclear membrane.

She also found something remarkable. Proteins usually have a rigid structure, allowing them to interact with other molecules in specific orientations. However Heh2 transport depended on the presence of an unstructured region in the protein. Not only that, the unstructured region had to be of a sufficient length.

After further studies, she found how Heh2 was being transported across the nuclear membrane (see figure above). Before it crosses the membrane into the nucleus, the nuclear zip-code (NLS) gets bound to the karyopherin-α/β1 complex, which pulls the Heh2 across the nuclear membrane like a parental chaperone. However the NPC is a molecular sieve, with fibers (FG-Nups in the figure) that can block transport. To overcome this, Heh2 has unstructured regions which allows it to change shape for ease of passage through the fibers. After crossing the membrane, karyopherin-α/β1 releases the inner membrane protein Heh2.

Understanding nuclear import is important for several reasons. Firstly, the switches and signals that turn on genes often need to be transported into the nucleus. Secondly, viruses often hitchhike on the nuclear import machinery to be able to hijack the nucleus and produce hundreds of copies of itself. By studying this process, one day we may be able to design drugs to prevent entry of those signals or viruses during diseases.


Meinema, A., et al. (2011). Long Unfolded Linkers Facilitate Membrane Protein Import Through the Nuclear Pore Complex. Science 333(6038): 90-93. Paper.