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Ran (biology)
Encyclopedia
Ran is a small 25Kda protein that is involved in transport into and out of the cell nucleus
during interphase
and also involved in mitosis
. It is a member of the Ras superfamily
.
Ran is a GTP
binding protein that is essential for the translocation of RNA and proteins through the nuclear pore complex. The Ran protein is also involved in control of DNA synthesis and cell cycle progression. Nuclear localization of Ran requires the presence of regulator of chromosome condensation 1 (RCC1
). Mutations in Ran disrupt DNA synthesis. Because of its many functions, it is likely that Ran interacts with several other proteins.
Ran exists in the cell in two nucleotide-bound forms: GDP
-bound and GTP
-bound. RanGDP is converted into RanGTP through the action of RCC1, the nucleotide exchange factor
for Ran. RCC1 is also known as RanGEF (Ran Guanine nucleotide Exchange Factor). Ran's intrinsic GTPase
-activity is activated through interaction with Ran GTPase activating protein
(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
and therefore located inside the nucleus
. 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 nuclear pore complex via interaction with the nucleoporin
RanBP2 (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 NTF2 (Nuclear Transport Factor 2), where RCC1 can then catalyze exchange of GTP for GDP on Ran.
Role in nuclear transport
Ran is involved in the transport of proteins across the nuclear envelope by interacting with karyopherin
s and changing their ability to bind or release cargo molecules. Cargo proteins containing a nuclear localization signal
(NLS) are bound by importin
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 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
assembly and nuclear envelope reassembly after the chromosomes have been separated. During prophase
, 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
s as RCC1, a nucleotide exchange factor, stays attached to chromatin
. RanBP2 (Nup358) and RanGAP move to the kinetochore
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 and TPX2 is inhibited by the binding to importins. By releasing importins, RanGTP activates these factors and therefore promotes the assembly of the mitotic spindle
. In telophase
, RanGTP hydrolysis and nucleotide exchange are required for vesicle fusion
at the reforming nuclear envelopes of the daughter nuclei.
(AR) coactivator
(ARA24) that binds differentially with different lengths of polyglutamine
within the androgen receptor. Polyglutamine repeat expansion in the AR is linked to Kennedy's disease
(X-linked spinal and bulbar muscular atrophy). 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 Kennedy's disease.
with XPO5
, RANGAP1
, XPO1
, KPNB1
, Transportin 1
, NUTF2
, RCC1
, RANBP1
, TNPO2
and NEK9
.
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
during interphase
Interphase
Interphase is the phase of the cell cycle in which the cell spends the majority of its time and performs the majority of its purposes including preparation for cell division. In preparation for cell division, it increases its size and makes a copy of its DNA...
and also involved in mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
. It is a member of the Ras superfamily
Ras superfamily
The Ras superfamily is a protein superfamily of small GTPases, which are all related, to a degree, to the Ras protein subfamily .There are more than a hundred proteins in the Ras superfamily...
.
Ran is a GTP
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
binding protein that is essential for the translocation of RNA and proteins through the nuclear pore complex. The Ran protein is also involved in control of DNA synthesis and cell cycle progression. Nuclear localization of Ran requires the presence of regulator of chromosome condensation 1 (RCC1
RCC1
Regulator of chromosome condensation 1, also known as RCC1, is the name for a human gene and protein.RCC1 also functions as a guanine nucleotide exchange factor for Ran GTPase.-Interactions:...
). Mutations in Ran disrupt DNA synthesis. Because of its many functions, it is likely that Ran interacts with several other proteins.
Ran cycle
Guanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase guanine....
-bound and GTP
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
-bound. RanGDP is converted into RanGTP through the action of RCC1, the nucleotide exchange factor
Nucleotide exchange factor
Nucleotide exchange factors are proteins that stimulate the exchange of nucleoside diphosphates for nucleoside triphosphates bound to other proteins.-Function:...
for Ran. RCC1 is also known as RanGEF (Ran Guanine nucleotide Exchange Factor). Ran's intrinsic GTPase
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
-activity is activated through interaction with Ran GTPase activating protein
GTPase activating protein
GTPase-Activating Proteins, or GAPs, or GTPase-Accelerating Proteins 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...
(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
RCC1
Regulator of chromosome condensation 1, also known as RCC1, is the name for a human gene and protein.RCC1 also functions as a guanine nucleotide exchange factor for Ran GTPase.-Interactions:...
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
RCC1
Regulator of chromosome condensation 1, also known as RCC1, is the name for a human gene and protein.RCC1 also functions as a guanine nucleotide exchange factor for Ran GTPase.-Interactions:...
is bound to chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
and therefore located inside the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
. RanGAP is cytoplasmic in yeast and bound to the nuclear envelope
Nuclear envelope
A nuclear envelope is a double lipid bilayer that encloses the genetic material in eukaryotic cells. The nuclear envelope also serves as the physical barrier, separating the contents of the nucleus from the cytosol...
in plants and animals. In mammalian cells, it is SUMO modified and attached to the cytoplasmic side of the nuclear pore complex via interaction with the nucleoporin
Nucleoporin
The nucleoporins are a family of proteins which are the constituent building blocks of the nuclear pore complex. The nuclear pore complex is a massive structure that extends across the nuclear envelope, forming a gateway that regulates the flow of macromolecules between the cell nucleus and the...
RanBP2 (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 NTF2 (Nuclear Transport Factor 2), where RCC1 can then catalyze exchange of GTP for GDP on Ran.
Role in nuclear transportNuclear transportThe entry and exit of large molecules from the cell nucleus is tightly controlled by the nuclear pore complexes . Although small molecules can enter the nucleus without regulation, macromolecules such as RNA and proteins require association with karyopherins called importins to enter the nucleus...
during interphaseInterphaseInterphase is the phase of the cell cycle in which the cell spends the majority of its time and performs the majority of its purposes including preparation for cell division. In preparation for cell division, it increases its size and makes a copy of its DNA...
Karyopherin
Karyopherins are a group of proteins involved in transporting molecules from the cytoplasm into the nucleus of eukaryotic cells. The inside of the nucleus is called the karyoplasm . Generally, karyopherin-mediated transport occurs through the nuclear pore, which acts as a gateway into and out of...
s and changing their ability to bind or release cargo molecules. Cargo proteins containing a nuclear localization signal
Nuclear localization signal
A nuclear localization signal or sequence is an amino acid sequence which '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 or arginines exposed on the protein surface. Different...
(NLS) are bound by importin
Importin
Importin is a type of protein that moves other protein molecules into the nucleus by binding to a specific recognition sequence, called the nuclear localization signal . Importin is classified as a karyopherin....
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 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 mitosisMitosisMitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
During mitosis, the Ran cycle is involved in mitotic spindleMitotic spindle
In cell biology, the spindle fibers are the structure that separates the chromosomes into the daughter cells during cell division. It is part of the cytoskeleton in eukaryotic cells...
assembly and nuclear envelope reassembly after the chromosomes have been separated. During prophase
Prophase
Prophase, from the ancient Greek πρό and φάσις , is a stage of mitosis in which the chromatin condenses into a highly ordered structure called a chromosome in which the chromatin becomes visible. This process, called chromatin condensation, is mediated by the condensin complex...
, 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
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
s as RCC1, a nucleotide exchange factor, stays attached to chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
. RanBP2 (Nup358) and RanGAP move to the kinetochore
Kinetochore
The kinetochore is the protein structure on chromatids where the spindle fibers attach during cell division to pull sister chromatids apart....
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 and TPX2 is inhibited by the binding to importins. By releasing importins, RanGTP activates these factors and therefore promotes the assembly of the mitotic spindle
Mitotic spindle
In cell biology, the spindle fibers are the structure that separates the chromosomes into the daughter cells during cell division. It is part of the cytoskeleton in eukaryotic cells...
. In telophase
Telophase
Telophase from the ancient Greek "τελος" and "φασις" , is a stage in both meiosis and mitosis in a eukaryotic cell. During telophase, the effects of prophase and prometaphase events are reversed. Two daughter nuclei form in the cell. The nuclear envelopes of the daughter cells are formed from the...
, RanGTP hydrolysis and nucleotide exchange are required for vesicle fusion
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 at the porosome...
at the reforming nuclear envelopes of the daughter nuclei.
Ran and the androgen receptor
RAN is an androgen receptorAndrogen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
(AR) coactivator
Coactivator (genetics)
A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
(ARA24) that binds differentially with different lengths of polyglutamine
Polyglutamine tract
A polyglutamine tract or polyQ tract is a portion of a protein consisting of a sequence of several glutamine units. A tract typically consists of about 10 to a few hundred such units....
within the androgen receptor. Polyglutamine repeat expansion in the AR is linked to Kennedy's disease
Kennedy disease
Kennedy's disease or X-linked Spinal and Bulbar Muscular Atrophy or Spinobulbar Muscular Atrophy or X-Linked Bulbo-Spinal Atrophy is an X-linked recessive, slow progressing, neurodegenerative disease associated with mutation of the androgen receptor...
(X-linked spinal and bulbar muscular atrophy). 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 Kennedy's disease.
Interactions
Ran (biology) has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with XPO5
XPO5
Exportin-5 is a protein that in humans is encoded by the XPO5 gene.-Interactions:XPO5 has been shown to interact with ILF3 and Ran .-Further reading:...
, RANGAP1
RANGAP1
Ran GTPase-activating protein 1 is an enzyme that in humans is encoded by the RANGAP1 gene.-Interactions:RANGAP1 has been shown to interact with Ran and UBE2I.-Further reading:...
, XPO1
XPO1
Exportin-1 is a protein that in humans is encoded by the XPO1 gene.-Interactions:XPO1 has been shown to interact with NMD3, CIITA, RANBP3, Nucleoporin 62, Ran, RANBP1, APC, SMARCB1 and CDKN1B.-Further reading:...
, KPNB1
KPNB1
Importin subunit beta-1 is a protein that in humans is encoded by the KPNB1 gene.-Interactions:KPNB1 has been shown to interact with NUP98, Karyopherin alpha 1, KPNA3, Karyopherin alpha 2, SMN1, Parathyroid hormone-related protein, Nucleoporin 62, RANBP2, Ran , RANBP1, NUP50, P53, NUP153 and...
, Transportin 1
Transportin 1
Transportin-1 is a protein that in humans is encoded by the TNPO1 gene.-Interactions:Transportin 1 has been shown to interact with RGPD5 and Ran .-Further reading:...
, NUTF2
NUTF2
Nuclear transport factor 2 is a protein that in humans is encoded by the NUTF2 gene.-Interactions:NUTF2 has been shown to interact with Nucleoporin 62 and Ran .-Further reading:...
, RCC1
RCC1
Regulator of chromosome condensation 1, also known as RCC1, is the name for a human gene and protein.RCC1 also functions as a guanine nucleotide exchange factor for Ran GTPase.-Interactions:...
, RANBP1
RANBP1
Ran-specific binding protein 1 is an enzyme that in humans is encoded by the RANBP1 gene.-Interactions:RANBP1 has been shown to interact with XPO1, KPNB1 and Ran.-Further reading:...
, TNPO2
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 .-Further reading:...
and NEK9
NEK9
Serine/threonine-protein kinase Nek9 is an enzyme that in humans is encoded by the NEK9 gene.-Interactions:NEK9 has been shown to interact with Structure specific recognition protein 1, NEK6 and Ran .-Further reading:...
.
Regulation
The expression of Ran is repressed by the microRNA miR-10a.See also
- small GTPaseSmall GTPaseSmall GTPases are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . They are a form of G-proteins found in the cytosol which are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function...
- GTPaseGTPaseGTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
- nuclear transportNuclear transportThe entry and exit of large molecules from the cell nucleus is tightly controlled by the nuclear pore complexes . Although small molecules can enter the nucleus without regulation, macromolecules such as RNA and proteins require association with karyopherins called importins to enter the nucleus...
- nuclear envelopeNuclear envelopeA nuclear envelope is a double lipid bilayer that encloses the genetic material in eukaryotic cells. The nuclear envelope also serves as the physical barrier, separating the contents of the nucleus from the cytosol...
- mitosisMitosisMitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
- importinImportinImportin is a type of protein that moves other protein molecules into the nucleus by binding to a specific recognition sequence, called the nuclear localization signal . Importin is classified as a karyopherin....
- RGPD5RGPD5RANBP2-like and GRIP domain-containing protein 5 is a protein that in humans is encoded by the RGPD5 gene.-Interactions:RGPD5 has been shown to interact with Transportin 1.-Further reading:...