Regulation of the Directionality of Nuclear Transport by Ran

(Nakielny and Dreyfuss 1999)

The directionality of classical nuclear transport is influenced by Ran.

Other proteins involved:

· RCC1: Guanine nucleotide exchange factor of Ran

Located in the nucleus

RCC1 accelerates dissociation of guanine nucleotides

The reaction to form Ran-GDP from Ran-GTP occurs because GTP is at higher levels than GDP

· RanGAP: GTPase activating protein of Ran

· RanBP1 and RanBP2: Ran-GTP binding proteins

Cofactors for RanGAP activation

RanBP1 located in cytoplasm (has NES)

RanBP2 located on cytoplasmic fibrils of NPC

Therefore, RanGDP located only in cytoplasm

Summary:

· Cytoplasmic Ran is mainly GDP-bound

· Nuclear Ran is GTP-bound

· This creates steep gradient for RanGDP/GTP across the nuclear envelope

(Yoneda 2000)

IMPORT

1. Import receptors bind to cargo in cytoplasm and are transported to the nucleus

2. In the nucleus (high [Ran-GTP]), Ran-GTP binds importins, which causes cargo to dissociate.

3. Importins are transported to the cytosol wtih Ran-GTP bound.

4. RanGAP and RanBP1 catalyze the formation of Ran-GDP from Ran-GTP.

5. Receptors can bind another cargo molecule.

EXPORT

1. Exportins bind Ran-GTP and a cargo molecule in the nucleus.

2. Transport through the NPC can occur.

3. RanGAP causes hydrolysis of Ran-GTP to Ran-GDP in the cytoplasm.

4. The cargo molecule dissociates from the complex.

(Dasso 2002)