RAN

Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases

• SMART accession number: SM00176
• Description: Ran is involved in the active transport of proteins through nuclear pores.

There are 1762 RAN domains in 1750 proteins in SMART's nrdb database.

Cellular role (predicted cellular role)

Binding / catalysis: GTP-hydrolysis

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Yaseen NR, Blobel G
• Two distinct classes of Ran-binding sites on the nucleoporin Nup-358.
• Proc Natl Acad Sci U S A. 1999; 96: 5516-21

Nup-358 is a giant nucleoporin located at the tips of the cytoplasmic fibrils of the nuclear pore complex (NPC). Its contains four RBH (RanBP1-homologous) domains and a zinc finger domain with eight zinc finger motifs. Using three recombinant fragments of Nup-358 that comprise two of the RBH domains and the zinc finger domain, we show that both RanGDP and RanGTP bind to Nup-358 in vitro. The RBH domains bound either RanGDP or RanGTP. Interestingly, the zinc finger domain was found to bind RanGDP exclusively. Zinc chelation by EDTA treatment abolished the binding of RanGDP to the zinc finger domain without affecting the binding of Ran to the RBH domain. Ultrastructural studies with RanGDP-conjugated colloidal gold in digitonin-permeabilized cells showed a large number of Ran-binding sites on the cytoplasmic fibrils of the NPC. Of those, only a portion that is closer to the central axis of the NPC was sensitive to RanBP1 competition, suggesting that most of the RBH domains of Nup-358 are situated closer to the central axis of the NPC than the zinc finger domain. Thus, the RBH and the zinc finger domains of Nup-358 were identified as two different classes of Ran-binding sites with distinct, ultrastructural locations at the NPC.

• Richards SA, Carey KL, Macara IG
• Requirement of guanosine triphosphate-bound ran for signal-mediated nuclear protein export.
• Science. 1997; 276: 1842-4

A leucine-rich nuclear export signal (NES) allows rapid export of proteins from cell nuclei. Microinjection studies revealed a role for the guanosine triphosphatase (GTPase) Ran in NES-mediated export. Nuclear injection of a Ran mutant (Thr24 --> Asn) blocked protein export but not import, whereas depletion of the Ran nucleotide exchange factor RCC1 blocked protein import but not export. However, injection of Ran GTPase-activating protein (RanGAP) into RCC1-depleted cell nuclei inhibited export. Coinjection with Ran mutants insensitive to RanGAP prevented this inhibition. Therefore, NES-mediated protein export appears to require a Ran-GTP complex but does not require Ran-dependent GTP hydrolysis.

• Yoneda Y
• How proteins are transported from cytoplasm to the nucleus.
• J Biochem (Tokyo). 1997; 121: 811-7

Nuclear proteins are transported actively through nuclear pores by a selective, mediated process. The process is mediated by a nuclear localization signal (NLS), and can be divided into at least two steps, (a) targeting to the pores and (b) translocation through the pores. The first step involves the formation of a stable complex containing a nuclear protein, termed nuclear pore-targeting complex (PTAC), in the cytoplasm. The second step, translocation, requires at least two soluble factors, a small GTPase Ran and its interacting protein p10/nuclear transport factor 2 (NTF2), along with nuclear pore complex components. These findings have been generally obtained by using the NLS of SV40 large T-antigen, and data concerning the detailed mechanism are now accumulating. Transport pathways other than for the SV40 T-antigen, for example, extracellular signal-dependent nuclear protein import pathway, have also recently been studied. Considering all these observations, one should be able to attain an understanding of the mechanism of intracellular information transduction between cytoplasm and the nucleus.

• Koepp DM, Silver PA
• A GTPase controlling nuclear trafficking: running the right way or walking RANdomly?
• Cell. 1996; 87: 1-4

• Lounsbury KM, Richards SA, Carey KL, Macara IG
• Mutations within the Ran/TC4 GTPase. Effects on regulatory factor interactions and subcellular localization.
• J Biol Chem. 1996; 271: 32834-41

Ran, a member of the Ras superfamily of GTPases, is predominantly localized in the nucleus and is a necessary component in the active transport of proteins through nuclear pores. Disruption of Ran function affects the regulation of mitosis, DNA synthesis, and RNA processing and export. To explore the mechanisms of Ran function, mutants of the Ran GTPase were characterized, several of which are capable of dominantly interfering with nuclear protein import. Unlike wild-type Ran, the putative gain-of-function mutant (G19V Ran) was not sensitive to the exchange factor, RCC1. In addition the G19V Ran and effector domain mutants (L43E and E46G Ran) were not sensitive to the GTPase-activating protein, Fug1. Epitope-tagged G19V Ran and L43E Ran isolated from transfected BHK21 cells were each about 50% GTP-bound, whereas the wild-type and a C-terminal deletion mutant (Delta-DE Ran) were primarily bound to GDP. While G19V Ran interacted with known Ran-binding proteins and with an isolated Ran-binding domain, the T24N Ran did not, and binding by L43E Ran was substantially reduced. Wild-type HA1-tagged Ran expressed in BHK21 cells was nuclear, whereas the G19V, T24N, L43E, and E46G forms of Ran were predominantly localized at the nuclear envelope, and Delta-DE Ran was primarily cytosolic. Similar results were observed when permeabilized BHK21 cells were incubated with extracts of COS cells expressing the mutants. Thus mutations that affect the interaction of Ran with regulatory proteins and effectors can disrupt the normal subcellular localization of Ran, lending support for the current model of Ran-mediated nuclear import.

• Scheffzek K, Klebe C, Fritz-Wolf K, Kabsch W, Wittinghofer A
• Crystal structure of the nuclear Ras-related protein Ran in its GDP-bound form.
• Nature. 1995; 374: 378-81

The Ran proteins constitute a distinct branch of the superfamily of Ras-related GTP-binding proteins which function as molecular switches cycling between GTP-bound 'on' and GDP-bound 'off' states. Ran is located predominantly in the nucleus of eukaryotic cells and is involved in the nuclear import of proteins as well as in control of DNA synthesis and of cell-cycle progression. We report here the crystal structure at 2.3 A resolution of human Ran (Mr 24K) complexed with GDP and Mg2+. This structure reveals a similarity with the Ras core (G-domain) but with significant variations in regions involved in GDP and Mg2+ coordination (switch I and switch II regions in Ras), suggesting that there could be major conformational changes upon GTP binding. In addition to the G-domain, an extended chain and an alpha-helix were identified at the carboxy terminus. The amino-terminal (amino-acid residues MAAQGEP) stretch and the acidic tail (DEDDDL) appear to be flexible in the crystal structure.

• Matsumoto T, Beach D
• Premature initiation of mitosis in yeast lacking RCC1 or an interacting GTPase.
• Cell. 1991; 66: 347-60

A fission yeast mutant is described in which the onset of mitosis is uncoupled from the completion of DNA replication. pim1 (premature initiation of mitosis) cells can undergo mitotic chromosome condensation and mitotic spindle formation without completion of S phase and without the cdc25 mitotic inducer. The M phase kinase is required for pim1-induced mitosis and becomes activated. pim1 encodes a homolog of the human RCC1 nuclear protein. pim1 mutants are fully rescued by overexpression of spi1, a newly identified essential gene whose predicted product shares 81% identity with human TC4. spi1 and TC4 define a new subclass within the "ras-like" GTPase superfamily that is structurally distinct from the ras, rho, or sec4 families. Diploid yeast that carry one wild-type and one disrupted copy of spi1 have multiple satellite nuclei, and mitotic haploidization occurs at very high frequency. spi1 appears to interact with pim1 in the maintenance of a coordinated cell cycle.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the RAN domain.

Protein	Disease
Ras-related protein Rab-27A (P51159) (SMART)	OMIM:603868: Griscelli syndrome OMIM:214450:
GTPase HRas (P01112) (SMART)	OMIM:190020: Bladder cancer OMIM:109800:
GTPase NRas (P01111) (SMART)	OMIM:164790: Colorectal cancer
GTPase KRas (P01116) (SMART)	OMIM:190070: Colorectal adenoma ; Colorectal cancer
Ras-related protein R-Ras2 (P62070) (SMART)	OMIM:600098: ONCOGENE TC21
UNKNOWN (SMART)	OMIM:190070: Colorectal adenoma ; Colorectal cancer

Structure (3D structures containing this domain)

3D Structures of RAN domains in PDB

PDB code	Title
1a2k	GDPRAN-NTF2 COMPLEX
1byu	CANINE GDP-RAN
1i2m	RAN-RCC1-SO4 COMPLEX
1ibr	COMPLEX OF RAN WITH IMPORTIN BETA
1k5d	Crystal structure of Ran-GPPNHP-RanBP1-RanGAP complex
1k5g	Crystal structure of Ran-GDP-AlFx-RanBP1-RanGAP complex
1qbk	STRUCTURE OF THE KARYOPHERIN BETA2-RAN GPPNHP NUCLEAR TRANSPORT COMPLEX
1qg2	CANINE GDP-RAN R76E MUTANT
1qg4	CANINE GDP-RAN F72Y MUTANT
1rrp	STRUCTURE OF THE RAN-GPPNHP-RANBD1 COMPLEX
1wa5	Crystal structure of the exportin Cse1p complexed with its cargo ( Kap60p) and RanGTP
2bku	Kap95p:RanGTP complex
2mmc	2MMC
2mmg	2MMG
2n1b	2N1B
2x19	Crystal structure of Importin13 - RanGTP complex
3a6p	Crystal structure of Exportin-5:RanGTP:pre-miRNA complex
3ch5	The crystal structure of the RanGDP-Nup153ZnF2 complex
3ea5	Kap95p Binding Induces the Switch Loops of RanGDP to adopt the GTP-bound Conformation: Implications for Nuclear Import Complex Assembly Dynamics
3gj0	Crystal structure of human RanGDP
3gj3	Crystal structure of human RanGDP-Nup153ZnF2 complex
3gj4	Crystal structure of human RanGDP-Nup153ZnF3 complex
3gj5	Crystal structure of human RanGDP-Nup153ZnF4 complex
3gj6	Crystal structure of human RanGDP-Nup153ZnF1 complex
3gj7	Crystal structure of human RanGDP-Nup153ZnF12 complex
3gj8	Crystal structure of human RanGDP-Nup153ZnF34 complex
3gjx	Crystal Structure of the Nuclear Export Complex CRM1-Snurportin1-RanGTP
3icq	Karyopherin nuclear state
3m1i	Crystal structure of yeast CRM1 (Xpo1p) in complex with yeast RanBP1 (Yrb1p) and yeast RanGTP (Gsp1pGTP)
3nby	Crystal structure of the PKI NES-CRM1-RanGTP nuclear export complex
3nbz	Crystal structure of the HIV-1 Rev NES-CRM1-RanGTP nuclear export complex (crystal I)
3nc0	Crystal structure of the HIV-1 Rev NES-CRM1-RanGTP nuclear export complex (crystal II)
3nc1	Crystal structure of the CRM1-RanGTP complex
3ran	CANINE GDP-RAN Q69L MUTANT
3w3z	Crystal structure of Kap121p bound to RanGTP
3wyf	3WYF
3wyg	3WYG
3zjy	Crystal Structure of Importin 13 - RanGTP - eIF1A complex
4c0q	Transportin 3 in complex with Ran(Q69L)GTP
4djt	Crystal structure of a nuclear GTP-binding protein from Encephalitozoon cuniculi bound to GDP-Mg2+
4gmx	Crystal structure of KPT185 in complex with CRM1-Ran-RanBP1
4gpt	Crystal structure of KPT251 in complex with CRM1-Ran-RanBP1
4hat	Crystal structure of CRM1 inhibitor Leptomycin B in complex with CRM1-Ran-RanBP1
4hau	Crystal structure of CRM1 inhibitor Ratjadone A in complex with CRM1-Ran-RanBP1
4hav	Crystal structure of CRM1 inhibitor Anguinomycin A in complex with CRM1-Ran-RanBP1
4haw	Crystal structure of CRM1 inhibitor Leptomycin B in complex with CRM1(K548A)-Ran-RanBP1
4hax	Crystal structure of CRM1 inhibitor Ratjadone A in complex with CRM1(K579A)-Ran-RanBP1
4hay	Crystal structure of CRM1 inhibitor Leptomycin B in complex with CRM1(K548E,K579Q)-Ran-RanBP1
4haz	Crystal structure of CRM1 inhibitor Leptomycin B in complex with CRM1(R543S,K548E,K579Q)-Ran-RanBP1
4hb0	Crystal structure of CRM1 inhibitor Leptomycin B in complex with CRM1(K541Q,K542Q,R543S,K545Q,K548Q,K579Q)-Ran-RanBP1
4hb2	Crystal structure of CRM1-Ran-RanBP1
4hb3	Crystal structure of CRM1(T539S)-Ran-RanBP1 with weakly bound unmodeled Leptomycin B
4hb4	Crystal structure of CRM1 inhibitor Leptomycin B in complex with CRM1(537DLTVK541/GLCEQ)-Ran-RanBP1
4ol0	Crystal structure of transportin-SR2, a karyopherin involved in human disease, in complex with Ran
4wvf	4WVF
5bxq	5BXQ
5ciq	5CIQ
5cit	5CIT
5ciw	5CIW
5cj2	5CJ2
5cll	5CLL
5clq	5CLQ
5dh9	5DH9
5dha	5DHA
5dhf	5DHF
5di9	5DI9
5dif	5DIF
5dis	5DIS
5dlq	5DLQ
5jlj	5JLJ