At least four mechanisms can usher inner nuclear membrane (INM) proteins to their proper location, Zuleger et al. show.
A freshly made membrane protein can diffuse through the ER to the outer nuclear membrane (ONM), but reaching the INM is trickier. Researchers think that proteins cross from the ONM to the INM via nuclear pore complexes. However, instead of using the pore's front door, the central channel, they use peripheral channels as side entrances. How proteins traverse these small-bore structures has remained mysterious. Some previous studies suggested that proteins diffuse between the ONM and INM, whereas other work indicated that this movement requires ATP or the nuclear transport factor Ran.
Zuleger et al. performed photobleaching experiments to test the different proposed mechanisms for six INM proteins. Two proteins required ATP but not Ran to reach their destination. Another protein needed Ran but not ATP. The remaining three proteins apparently traveled by diffusion.
When helping to ship proteins through the central nuclear pore channel, Ran separates a soluble cargo molecule from its transport receptor after the pair have crossed the channel. But the combination of Ran, a transport receptor, and an INM protein is too hefty to fit through the narrow peripheral channels. Thus Ran might function differently during peripheral channel transport.
A fourth mechanism also could give certain INM proteins a helping hand. The researchers found that proteins moved faster when they carried stretches of phenylalanine-glycine repeats, and this effect disappeared when a peripheral channel nucleoporin that also sports the repeats was absent. Interactions between these repeats might allow INM proteins to function as their own transport receptors.