Ran (RAs-related Nuclear protein) also known as GTP-binding nuclear protein Ran is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the RAN

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. Ran is a small 25 kDa protein that is involved in transport into and out of the cell nucleus during

interphase Interphase is the portion of the cell cycle that is not accompanied by visible changes under the microscope, and includes the G1, S and G2 phases. During interphase, the cell grows (G1), replicates its DNA (S) and prepares for mitosis (G2). A c ...

and also involved in mitosis. It is a member of the

Ras superfamily The Ras superfamily, derived from "Rat sarcoma virus", is a protein superfamily of small GTPases. Members of the superfamily are divided into families and subfamilies based on their structure, sequence and function. The five main families are Ra ...

. Ran is a

small G protein Small GTPases (), also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotr ...

that is essential for the translocation of RNA and proteins through the

nuclear pore complex A nuclear pore is a part of a large complex of proteins, known as a nuclear pore complex that spans the nuclear envelope, which is the double membrane surrounding the eukaryotic cell nucleus. There are approximately 1,000 nuclear pore complexe ...

. The Ran protein has also been implicated in the control of DNA synthesis and cell cycle progression, as mutations in Ran have been found to disrupt DNA synthesis.

Function

Ran cycle

Ran exists in the cell in two nucleotide-bound forms:

GDP Gross domestic product (GDP) is a monetary measure of the market value of all the final goods and services produced and sold (not resold) in a specific time period by countries. Due to its complex and subjective nature this measure is ofte ...

-bound and GTP-bound. RanGDP is converted into RanGTP through the action of

RCC1 Regulator of chromosome condensation 1, also known as RCC1, Ran guanine nucleotide exchange factor and RanGEF, is the name for a human gene and protein. RCC1 also functions as a guanine nucleotide exchange factor for Ran GTPase. Interactions ...

, the nucleotide exchange factor for Ran. RCC1 is also known as RanGEF (Ran Guanine nucleotide Exchange Factor). Ran's intrinsic

GTPase GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...

-activity is activated through interaction with Ran

GTPase activating protein GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are ...

(RanGAP), facilitated by complex formation with Ran-binding protein (RanBP). GTPase-activation leads to the conversion of RanGTP to RanGDP, thus closing the Ran cycle. Ran can diffuse freely within the cell, but because RCC1 and RanGAP are located in different places in the cell, the concentration of RanGTP and RanGDP differs locally as well, creating concentration gradients that act as signals for other cellular processes. RCC1 is bound to

chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...

and therefore located inside the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom * Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...

. RanGAP is cytoplasmic in yeast and bound to the nuclear envelope in plants and animals. In mammalian cells, it is SUMO modified and attached to the cytoplasmic side of the

via interaction with the

nucleoporin Nucleoporins are a family of proteins which are the constituent building blocks of the nuclear pore complex (NPC). The nuclear pore complex is a massive structure embedded in the nuclear envelope at sites where the inner and outer nuclear membra ...

RANBP2 RAN binding protein 2 (RANBP2) is protein which in humans is encoded by the ''RANBP2'' gene. It is also known as nucleoporin 358 (Nup358) since it is a member nucleoporin family that makes up the nuclear pore complex. RanBP2 has a mass of 358 kDa. ...

(Nup358). This difference in location of the accessory proteins in the Ran cycle leads to a high RanGTP to RanGDP ratio inside the nucleus and an inversely low RanGTP to RanGDP ratio outside the nucleus. In addition to a gradient of the nucleotide bound state of Ran, there is a gradient of the protein itself, with a higher concentration of Ran in the nucleus than in the cytoplasm. Cytoplasmic RanGDP is imported into the nucleus by the small protein

NUTF2 Nuclear transport factor 2 is a protein that in humans is encoded by the ''NUTF2'' gene. Function The protein encoded by this gene is a cytosolic factor that facilitates protein transport into the nucleus. It interacts with the nuclear pore co ...

(Nuclear Transport Factor 2), where RCC1 can then catalyze exchange of GDP for GTP on Ran.

Role in nuclear transport during interphase

'' Ran is involved in the transport of proteins across the nuclear envelope by interacting with

karyopherin Karyopherins are proteins involved in transporting molecules between the cytoplasm and the nucleus of a eukaryotic cell. The inside of the nucleus is called the karyoplasm (or nucleoplasm). Generally, karyopherin-mediated transport occurs through ...

s and changing their ability to bind or release cargo molecules. Cargo proteins containing a

nuclear localization signal A nuclear localization signal ''or'' sequence (NLS) is an amino acid sequence that 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines o ...

(NLS) are bound by

importin Importin is a type of karyopherin that transports protein molecules from the cell's cytoplasm to the nucleus. It does so by binding to specific recognition sequences, called nuclear localization sequences (NLS). Importin has two subunits, impo ...

s and transported into the nucleus. Inside the nucleus, RanGTP binds to importin and releases the import cargo. Cargo that needs to get out of the nucleus into the cytoplasm binds to

exportin Karyopherins are proteins involved in transporting molecules between the cytoplasm and the nucleus of a eukaryotic cell. The inside of the nucleus is called the karyoplasm (or nucleoplasm). Generally, karyopherin-mediated transport occurs through ...

in a ternary complex with RanGTP. Upon hydrolysis of RanGTP to RanGDP outside the nucleus, the complex dissociates and export cargo is released.

Role in mitosis

During mitosis, the Ran cycle is involved in

mitotic spindle In cell biology, the spindle apparatus refers to the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a pr ...

assembly and nuclear envelope reassembly after the chromosomes have been separated. During

prophase Prophase () is the first stage of cell division in both mitosis and meiosis. Beginning after interphase, DNA has already been replicated when the cell enters prophase. The main occurrences in prophase are the condensation of the chromatin ret ...

, the steep gradient in RanGTP-RanGDP ratio at the nuclear pores breaks down as the nuclear envelope becomes leaky and disassembles. RanGTP concentration stays high around the

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

s as RCC1, a nucleotide exchange factor, stays attached to

. RanBP2 (Nup358) and RanGAP move to the

kinetochore A kinetochore (, ) is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and ...

s where they facilitate the attachment of spindle fibers to chromosomes. Moreover, RanGTP promotes spindle assembly by mechanisms similar to mechanisms of nuclear transport: the activity of spindle assembly factors such as

NuMA Nuclear mitotic apparatus protein 1 is a protein that in humans is encoded by the ''NUMA1'' gene. Interactions Nuclear mitotic apparatus protein 1 has been shown to interact with PIM1, Band 4.1, GPSM2 G-protein-signaling modulator 2, also call ...

and

TPX2 Targeting protein for Xklp2 is a protein that in humans is encoded by the ''TPX2'' gene. It is one of the many spindle assembly factors that play a key role in inducing microtubule assembly and growth during M phase. Key domains of TPX2 TPX2 has ...

is inhibited by the binding to importins. By releasing importins, RanGTP activates these factors and therefore promotes the assembly of the

. In

telophase Telophase () is the final stage in both meiosis and mitosis in a eukaryotic cell. During telophase, the effects of prophase and prometaphase (the nucleolus and nuclear membrane disintegrating) are reversed. As chromosomes reach the cell poles, ...

, RanGTP hydrolysis and nucleotide exchange are required for

vesicle fusion Vesicle fusion is the merging of a vesicle with other vesicles or a part of a cell membrane. In the latter case, it is the end stage of secretion from secretory vesicles, where their contents are expelled from the cell through exocytosis. Vesicles c ...

at the reforming nuclear envelopes of the daughter nuclei.

Ran and the androgen receptor

RAN is an androgen receptor (AR)

coactivator A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA ...

(ARA24) that binds differentially with different lengths of polyglutamine within the androgen receptor. Polyglutamine repeat expansion in the AR is linked to

spinal and bulbar muscular atrophy Spinal and bulbar muscular atrophy (SBMA), popularly known as Kennedy's disease, is a debilitating neurodegenerative disorder resulting in muscle cramps and progressive weakness due to degeneration of motor neurons in the brainstem and spinal cor ...

(Kennedy's disease). RAN coactivation of the AR diminishes with polyglutamine expansion within the AR, and this weak coactivation may lead to partial androgen insensitivity during the development of spinal and bulbar muscular atrophy.

Interactions

Ran has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: *

KPNB1 Importin subunit beta-1 is a protein that in humans is encoded by the ''KPNB1'' gene. Function Nucleocytoplasmic transport, a signal- and energy-dependent process, takes place through nuclear pore complexes embedded in the nuclear envelope. ...

, * NEK9, *

, *

RANBP1 Ran-specific binding protein 1 is an enzyme that in humans is encoded by the ''RANBP1'' gene. Ran/TC4-binding protein, RanBP1, interacts specifically with GTP-charged RAN. RANBP1 encodes a 23-kD protein that binds to RAN complexed with GTP but n ...

, *

RANGAP1 Ran GTPase-activating protein 1 is an enzyme that in humans is encoded by the ''RANGAP1'' gene. Function RanGAP1, is a homodimeric 65-kD polypeptide that specifically induces the GTPase activity of RAN, but not of RAS by over 1,000-fold. Ra ...

, *

, * TNPO1, *

TNPO2 Transportin-2 is a protein that in humans is encoded by the ''TNPO2'' gene. Interactions TNPO2 has been shown to interact with NXF1, NUP98 and Ran (biology) Ran (RAs-related Nuclear protein) also known as GTP-binding nuclear protein Ran is ...

, *

XPO1 Exportin 1 (XPO1), also known as chromosomal region maintenance 1 (CRM1), is a eukaryotic protein that mediates the nuclear export of various proteins and RNAs. History XPO1 (CRM1) originally was identified in the fission yeast ''Schizosaccharom ...

, and *

XPO5 gene ID :57510 Exportin-5 (XPO5) is a protein that, in humans, is encoded by the ''XPO5'' gene. In eukaryotic cells, the primary purpose of XPO5 is to export pre-microRNA (also known as pre-miRNA) out of the nucleus and into the cytoplasm, for fur ...

Regulation

The expression of Ran is repressed by the

microRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. mi ...

miR-10a.

References

External links

* * * {{Portal bar, Biology, border=no Cell biology Cell signaling G proteins