Neuropilin
Encyclopedia
Neuropilin is a protein
receptor
active in neuron
s.
There are two forms of Neuropilins, NRP-1
and NRP-2
. They are transmembrane glycoproteins, and predominantly co-receptor
s for another class of proteins known as semaphorin
s. Of the semaphorins, NRP-1 and NRP-2 are specifically receptors for class-3 semaphorins, which, amongst many things, are responsible for axon
guidance during the development of the nervous system
in vertebrate
s.
Neuropilins work as co-receptors as they have a very small cytoplasm
ic domain and thus rely upon other molecules to transduce their signals across a cell membrane
, normally plexins. Neuropilins generally work as dimer
s and different combinations have different affinities for molecules. For example, NRP-1 homodimers have high affinity for Sema-3A, whilst NRP-2 homodimers have high affinity for Sema-3F.
Another ligand for neuropilins is VEGF
, a growth factor involved in the regulation of angiogenesis
.
and lymphoma
, since It has been shown that there is increased expression in neuropilin-1 in leukemia and lymphoma cell lines. Also, antagonism
of neuropilin-1 has been found to inhibit tumour cell migration
and adhesion
.
The structure of B1 domain (coagulation factor 5/8 type) of neuropilin-1 was determined through X-Ray Diffraction with a resolution of 2.90 Å. The secondary structure of this domain is 5% alpha helical
and 46% beta sheet
.
Ramachandran plot.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
active in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s.
There are two forms of Neuropilins, NRP-1
Neuropilin 1
Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene.. This is one of two human neuropilins.-Interactions:Neuropilin 1 has been shown to interact with Vascular endothelial growth factor A.-Further reading:...
and NRP-2
NRP2
Neuropilin-2 is a protein that in humans is encoded by the NRP2 gene.-Further reading:...
. They are transmembrane glycoproteins, and predominantly co-receptor
Co-receptor
A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell.-Co-receptor Properties:...
s for another class of proteins known as semaphorin
Semaphorin
Semaphorins are a class of secreted and membrane proteins that act as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes. They are usually cues to deflect axons from inappropriate regions, especially...
s. Of the semaphorins, NRP-1 and NRP-2 are specifically receptors for class-3 semaphorins, which, amongst many things, are responsible for axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
guidance during the development of the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
in vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s.
Neuropilins work as co-receptors as they have a very small cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic domain and thus rely upon other molecules to transduce their signals across a cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
, normally plexins. Neuropilins generally work as dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
s and different combinations have different affinities for molecules. For example, NRP-1 homodimers have high affinity for Sema-3A, whilst NRP-2 homodimers have high affinity for Sema-3F.
Another ligand for neuropilins is VEGF
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
, a growth factor involved in the regulation of angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
.
Applications
Neuropilin-1 is a therapeutic target protein in the treatment for leukemiaLeukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
and lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
, since It has been shown that there is increased expression in neuropilin-1 in leukemia and lymphoma cell lines. Also, antagonism
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
of neuropilin-1 has been found to inhibit tumour cell migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
and adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
.
Structure
Neuropilins contain the following four domains:- N-terminal CUB domainCUB domainCUB domain is an evolutionary conserved protein domain.The CUB domain is a structural motif of approximately 110 residues found almost exclusively in extracellular and plasma membrane-associated proteins, many of which are developmentally regulated...
(for complement C1r/C1s, Uegf, Bmp1) - Coagulation factor 5/8 type, C-terminal (discoidin domainDiscoidin domainDiscoidin domain is major domain of many blood coagulation factors.Blood coagulation factors V and VIII contain a C-terminal, twice repeated, domain of about 150 amino acids, which is often called "C2-like domain"...
) - MAM domainMAM domainMAM domain is an evolutionary conserved protein domain. It is an extracellular domain found in many receptors. A 170 amino acid domain, the so-called MAM domain, has been recognised in the extracellular region of functionally diverse proteins...
(for meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu) - C-terminal neuropilin
The structure of B1 domain (coagulation factor 5/8 type) of neuropilin-1 was determined through X-Ray Diffraction with a resolution of 2.90 Å. The secondary structure of this domain is 5% alpha helical
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
and 46% beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
.
Ramachandran plot.