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Low-affinity nerve growth factor receptor
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Low-affinity nerve growth factor receptor
The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic factor receptor. Neurotrophic factor receptors bind Neurotrophins including Nerve growth factor, Neurotrophin-3, Brain-derived neurotrophic factor, and Neurotrophin-4. All neurotrophins bind to p75NTR. This also includes the immature pro-neurotrophin forms. Neurotrophic factor receptors, including p75NTR, are responsible for ensuring a proper density to target ratio of developing neurons, refining broader maps in development into precise connections. p75NTR is involved in pathways that promote neuronal survival and neuronal death.
p75NTR is a member of the tumor necrosis factor receptor superfamily. p75NTR/LNGFR was the first member of this large family of receptors to be characterized, that now contains about 25 receptors, including tumor necrosis factor 1 (TNFR1) and TNFR2, Fas, RANK, and CD40. All members of the TNFR superfamily contain structurally related cysteine-rich modules in their ECDs. p75NTR is an unusual member of this family due to its propensity to dimerize rather than trimerize, because of its ability to act as a tyrosine kinase co-receptor, and because the neurotrophins are structurally unrelated to the ligands, which typically bind TNFR family members. Indeed, with the exception of p75NTR, essentially all members of the TNFR family preferentially bind structurally related trimeric Type II transmembrane ligands, members of the TNF ligand superfamily.
p75NTR is a type I transmembrane protein, with a molecular weight of 75 kDa, determined by glycosylation through both N- and O-linkages in the extracellular domain. It consists of an extracellular domain, a transmembrane domain and an intracellular domain. The extracellular domain consists of a stalk domain connecting the transmembrane domain and four cysteine-rich repeat domains, CRD1, CRD2, CRD3, and CRD4; which are negatively charged, a property that facilitates Neurotrophin binding. The intracellular part is a global-like domain, known as a death domain, which consists of two sets of perpendicular helixes arranged in sets of three. It connects the transmembrane domain through a flexible linker region N-terminal domain. It is important to say that, in contrast to the type I death domain found in other TNFR proteins, the type II intracellular death domain of p75NTR does not self-associate. This was an early indication that p75NTR does not signal death through the same mechanism as the TNFR death domains, although the ability of the p75NTR death domain to activate other second messengers is conserved.
The p75ECD-binding interface to NT-3 can be divided into three main contact sites, two in the case of NGF, that are stabilized by hydrophobic interactions, salt bridges, and hydrogen bonds. The junction regions between CDR1 and CDR2 form the site 1 that contains five hydrogen bonds and one salt bridge. Site 2 is formed by equal contributions from CDR3 and CRD4 and involves two salt bridges and two hydrogen bonds. Site 3, in the CRD4, includes only one salt bridge.
Neurotrophins that interact with p75NTR include NGF, NT-3, BDNF, and NT-4/5. Neurotrophins activating p75NTR may initiate apoptosis (for example, via c-Jun N-terminal kinases signaling, and subsequent p53, Jax-like proteins and caspase activation). This effect can be counteracted by anti-apoptotic signaling by TrkA. Neurotrophin binding to p75NTR, in addition to apoptotic signaling, can also promote neuronal survival (for example, via NF-kB activation). There are multiple targets of Akt that could play a role in mediating p75NTR-dependent survival, but one of the more intriguing possibilities is that Ant-induced phosphorylation of IkB kinase 1 (IKK1) plays a role in the induction of NF-kB.
Proforms of NGF and BDNF (proNGF and proBDNF) are precursors to NGF and BDNF. proNGF and proBDNF interact with p75NTR and cause p75NTR-mediated apoptosis without activating TrkA-mediated survival mechanisms. Cleavage of proforms into mature Neurotrophins allows the mature NGF and BDNF to activate TrkA-mediated survival mechanisms.
Recent research has suggested a number of roles for the LNGFR, including in development of the eyes and sensory neurons, and in repair of muscle and nerve damage in adults. Two distinct subpopulations of Olfactory ensheathing glia have been identified with high or low cell surface expression of low-affinity nerve growth factor receptor (p75).
Sortilin is required for many apoptosis-promoting p75NTR reactions, functioning as a co-receptor for the binding of neurotrophins such as BDNF. pro-neurotrophins (such as proBDNF) bind especially well to p75NTR when sortilin is present.
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Low-affinity nerve growth factor receptor
The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic factor receptor. Neurotrophic factor receptors bind Neurotrophins including Nerve growth factor, Neurotrophin-3, Brain-derived neurotrophic factor, and Neurotrophin-4. All neurotrophins bind to p75NTR. This also includes the immature pro-neurotrophin forms. Neurotrophic factor receptors, including p75NTR, are responsible for ensuring a proper density to target ratio of developing neurons, refining broader maps in development into precise connections. p75NTR is involved in pathways that promote neuronal survival and neuronal death.
p75NTR is a member of the tumor necrosis factor receptor superfamily. p75NTR/LNGFR was the first member of this large family of receptors to be characterized, that now contains about 25 receptors, including tumor necrosis factor 1 (TNFR1) and TNFR2, Fas, RANK, and CD40. All members of the TNFR superfamily contain structurally related cysteine-rich modules in their ECDs. p75NTR is an unusual member of this family due to its propensity to dimerize rather than trimerize, because of its ability to act as a tyrosine kinase co-receptor, and because the neurotrophins are structurally unrelated to the ligands, which typically bind TNFR family members. Indeed, with the exception of p75NTR, essentially all members of the TNFR family preferentially bind structurally related trimeric Type II transmembrane ligands, members of the TNF ligand superfamily.
p75NTR is a type I transmembrane protein, with a molecular weight of 75 kDa, determined by glycosylation through both N- and O-linkages in the extracellular domain. It consists of an extracellular domain, a transmembrane domain and an intracellular domain. The extracellular domain consists of a stalk domain connecting the transmembrane domain and four cysteine-rich repeat domains, CRD1, CRD2, CRD3, and CRD4; which are negatively charged, a property that facilitates Neurotrophin binding. The intracellular part is a global-like domain, known as a death domain, which consists of two sets of perpendicular helixes arranged in sets of three. It connects the transmembrane domain through a flexible linker region N-terminal domain. It is important to say that, in contrast to the type I death domain found in other TNFR proteins, the type II intracellular death domain of p75NTR does not self-associate. This was an early indication that p75NTR does not signal death through the same mechanism as the TNFR death domains, although the ability of the p75NTR death domain to activate other second messengers is conserved.
The p75ECD-binding interface to NT-3 can be divided into three main contact sites, two in the case of NGF, that are stabilized by hydrophobic interactions, salt bridges, and hydrogen bonds. The junction regions between CDR1 and CDR2 form the site 1 that contains five hydrogen bonds and one salt bridge. Site 2 is formed by equal contributions from CDR3 and CRD4 and involves two salt bridges and two hydrogen bonds. Site 3, in the CRD4, includes only one salt bridge.
Neurotrophins that interact with p75NTR include NGF, NT-3, BDNF, and NT-4/5. Neurotrophins activating p75NTR may initiate apoptosis (for example, via c-Jun N-terminal kinases signaling, and subsequent p53, Jax-like proteins and caspase activation). This effect can be counteracted by anti-apoptotic signaling by TrkA. Neurotrophin binding to p75NTR, in addition to apoptotic signaling, can also promote neuronal survival (for example, via NF-kB activation). There are multiple targets of Akt that could play a role in mediating p75NTR-dependent survival, but one of the more intriguing possibilities is that Ant-induced phosphorylation of IkB kinase 1 (IKK1) plays a role in the induction of NF-kB.
Proforms of NGF and BDNF (proNGF and proBDNF) are precursors to NGF and BDNF. proNGF and proBDNF interact with p75NTR and cause p75NTR-mediated apoptosis without activating TrkA-mediated survival mechanisms. Cleavage of proforms into mature Neurotrophins allows the mature NGF and BDNF to activate TrkA-mediated survival mechanisms.
Recent research has suggested a number of roles for the LNGFR, including in development of the eyes and sensory neurons, and in repair of muscle and nerve damage in adults. Two distinct subpopulations of Olfactory ensheathing glia have been identified with high or low cell surface expression of low-affinity nerve growth factor receptor (p75).
Sortilin is required for many apoptosis-promoting p75NTR reactions, functioning as a co-receptor for the binding of neurotrophins such as BDNF. pro-neurotrophins (such as proBDNF) bind especially well to p75NTR when sortilin is present.
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