The 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 that extends across the nuclear envelope, forming a gateway that regulates the flow of macromolecules between the cell nucleus and the cytoplasm. Nuclear pores in turn allow the transport of water-soluble molecules across the nuclear envelope. Nucleoporins, a family of around 30 proteins, are the main components of the nuclear pore complex in eukaryotic cells. Nucleoporin 62 is the most abundant member of this family. Nucleoporins are able to transport molecules across the nuclear envelope at a very high rate. A single NPC is able to transport 60,000 protein molecules across the nuclear envelope every minute.
Nucleoporins mediate transport of macromolecules between the cell nucleus and cytoplasm in eukaryotes. Certain members of the nucleoporin family form the structural scaffolding of the nuclear pore complex. However, nucleoporins primarily function by interacting with transport molecules known as karyopherins, also known as Kaps These karyopherins interact with nucleoporins that contain FG peptide repeats, that is, they contain repeating sequences of the amino acids phenylalanine (F) and glycine (G). In doing so, karyopherins are able to shuttle their cargo across the nuclear envelope. Nucleoporins are only required for the transport of large hydrophilic molecules above 40 kDa, as smaller molecules pass through nuclear pores via passive diffusion. Nucleoporins play an important role in the transport of mRNA from the nucleus to the cytoplasm after transcription. Depending on their function, certain nucleoporins are localized to a single side of the nuclear pore complex, either cytosolic or nucleoplasmic. Other nucleoporins may be found on both faces.
All nucleoporins share some basic structural components. Like all proteins, nucleoporins are composed of strings of amino acids which are linked together by peptide bonds. Each nucleoporin consists of an N-terminus with a free amine group, a C-terminus with a free carboxyl group, and a central binding region. Nucleoporins aggregate to form a nuclear pore complex, an octagonal ring that traverses the nuclear envelope. There are three distinct types of nucleoporins that each have a unique structure and function. These three types are structural nucleoporins, membrane nucleoporins, and FG-nucleoporins.
Structural nucleoporins form the ring portion of the NPC. They span the membrane of the nuclear envelope and are often referred to as the scaffolding of a nuclear pore. Structural nucleoporins come together to form Y-complexes that are composed of seven nucleoporins. Each nuclear pore contains sixteen Y-complexes for a total of 112 structural nucleoporins. The structure of a Y-complex is highly similar to that of COPII. The relationship of the membrane curvature of a nuclear pore with Y-complexes can be seen as analogous to the budding formation of a COPII coated vesicle.
Membrane nucleoporins are localized to the curvature of a nuclear pore. These proteins are embedded within the nuclear membrane at the region where the inner and outer leaflets connect.
FG-nucleoporins are so named because they contain repeats of the amino acid residues phenylalanine and glycine. FG-repeats are small hydrophobic segments that break up long stretches of hydrophilic amino acids. These FG-repeat segments are found in long random-coil portions of the protein which stretch into the channel of nuclear pores and are primarily responsible for the selective exclusivity of nuclear pore complexes. These segments of FG-nucleoporins form a mass of chains which allow smaller molecules to diffuse through, but exclude large hydrophilic macromolecules. These large molecules are only able to cross a nuclear pore if they are accompanied by a signaling molecule that temporarily interacts with a nucleoporin's FG-repeat segment. FG-nucleoporins also contain a globular portion that serves as an anchor for attachment to the nuclear pore complex.
Nucleoporins have been shown to form various subcomplexes with one another. The most common of these complexes is the p62 complex, which is an assembly composed of NUP62, NUP58, NUP54 and NUP45. Another example of such a complex is the NUP107-160 complex, composed of many different nucleoporins. The NUP107-160 complex has been localized to kinetochores and plays a role in mitosis.
Nucleoporins regulate the transport of macromolecules through the nuclear envelope via interactions with the transporter molecules karyopherins. Karyopherins will bind to their cargo, and reversibly interact with the FG-repeats in nucleoporins. Karyopherins and their cargo are passed between FG-repeats until they diffuse down their concentration gradient and through the nuclear pore complex. Karyopherins can serve as an importin (transporting proteins into the nucleus) or an exportin (transporting proteins out of the nucleus). Karyopherins release of their cargo is driven by Ran, a G protein. Ran is small enough that it can diffuse through nuclear pores down its concentration gradient without interacting with nucleoporins. Ran will bind to either GTP or GDP and has the ability to change a karyopherin's affinity for its cargo. Inside the nucleus, RanGTP causes an importin karyopherin to change conformation, allowing its cargo to be released. RanGTP can also bind to exportin karyopherins and pass through the nuclear pore. Once it has reached the cytosol, RanGTP can be hydrolyzed to RanGDP, allowing the exportin's cargo to be released.
Several diseases have been linked to pathologies of nucleoporins, notably diabetes, primary biliary cirrhosis, Parkinson's Disease and Alzheimer's disease. Overexpression of the genes that encode for different nucleoporins also have been shown to be related to the formation of cancerous tumors.
Nucleoporins have been shown to be highly sensitive to glucose concentration changes. Therefore individuals affected by diabetes often exhibit increased glycosylation of nucleoporins, particularly nucleoporin 62.
Decreases in the production of the p62 complex are common to many neurodegenerative diseases. Modification of the p62 promoter by oxidation is correlated with Alzheimer's disease, Huntington's Disease, and Parkinson's disease among other neurodegenerative disorders.
Each individual nucleoporin is named according to its molecular weight (in kilo Daltons). Below are several examples of proteins in the nucleoporin family:
- NUP35, NUP37, NUP43, NUP50
- NUP54, NUP62, NUP85, NUP88, NUP93, NUP98
- NUP107, NUP133, NUP153, NUP155, NUP160, NUP188
- NUP205, NUP210, NUP214
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