Glial fibrillary acidic protein: Difference between revisions
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'''Glial fibrillary acidic protein''' (GFAP) is an [[intermediate filament]] (IF) [[protein]] that is found in [[glial cells]] such as [[astrocytes]]. First described in 1971<ref name="r2"> Fuchs |
'''Glial fibrillary acidic protein''' (GFAP) is an [[intermediate filament]] (IF) [[protein]] that is found in [[glial cells]] such as [[astrocytes]]. First described in 1971,<ref name="r2">{{cite journal | author = Fuchs E, Weber K | title = Intermediate filaments: structure, dynamics, function, and disease | journal = Annu. Rev. Biochem. | volume = 63 | issue = | pages = 345–82 | year = 1994 | pmid = 7979242 | doi = 10.1146/annurev.bi.63.070194.002021 | issn = }}</ref> GFAP is a type III IF protein that maps, in humans, to '''17q21'''. It is closely related to its non-epithelial family members, [[vimentin]], [[desmin]], and [[peripherin]], which are all involved in the structure and function of the cell’s [[cytoskeleton]]. GFAP helps to maintain [[astrocyte]] [[mechanical strength]], as well as the shape of cells. |
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==Structure== |
==Structure== |
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Type III intermediate filaments contain three domains, the most conserved of which is the rod domain. The specific [[DNA]] sequence for this region of the protein may differ between the different intermediate filament genes for type III proteins, but the structure of the protein is highly conserved. This rod domain coils around that of another filament to form a [[dimer]], with the [[N-terminal]] and [[C-terminal]] of each filament aligned. Type III filaments such as GFAP are capable of forming both homodimers and heterodimers; GFAP can polymerize with other type III proteins or with [[neurofilament]] protein (NF-L).<ref name="r3">Reeves |
Type III intermediate filaments contain three domains, the most conserved of which is the rod domain. The specific [[DNA]] sequence for this region of the protein may differ between the different intermediate filament genes for type III proteins, but the structure of the protein is highly conserved. This rod domain coils around that of another filament to form a [[dimer]], with the [[N-terminal]] and [[C-terminal]] of each filament aligned. Type III filaments such as GFAP are capable of forming both homodimers and heterodimers; GFAP can polymerize with other type III proteins or with [[neurofilament]] protein (NF-L).<ref name="r3">{{cite journal | author = Reeves SA, Helman LJ, Allison A, Israel MA | title = Molecular cloning and primary structure of human glial fibrillary acidic protein | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 86 | issue = 13 | pages = 5178–82 | year = 1989 | pmid = 2740350 | doi = 10.1073/pnas.86.13.5178 | issn = }}</ref> Interestingly, GFAP and other type III IF proteins cannot assemble with [[keratins]], the type I and II [[intermediate filament]]s. In cells that express both proteins, two separate intermediate filament networks form, which can allow for specialization and increased variability. |
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To form networks, the initial dimers combine to make staggered [[tetramer]]s, which are the basic subunits of an [[intermediate filament]]. Since rods alone in vitro do not form filaments, the non-helical domains are necessary for filament formation.<ref name="r3"/> The remaining two regions, head and tail, have greater variability of sequence and structure. However, the head of GFAP contains two [[arginine]]s and an [[aromatic]] residue that have been shown to be required for proper assembly.<ref name="r2"/> The sizes of the head and tail regions are quite different between GFAP and its more common counterpart [[vimentin]], which suggests that, when coassembled, they would align head-to-head rather than head-to-tail. This would allow for more plastic functionality of the intermediate filament network. |
To form networks, the initial dimers combine to make staggered [[tetramer]]s, which are the basic subunits of an [[intermediate filament]]. Since rods alone in vitro do not form filaments, the non-helical domains are necessary for filament formation.<ref name="r3"/> The remaining two regions, head and tail, have greater variability of sequence and structure. However, the head of GFAP contains two [[arginine]]s and an [[aromatic]] residue that have been shown to be required for proper assembly.<ref name="r2"/> The sizes of the head and tail regions are quite different between GFAP and its more common counterpart [[vimentin]], which suggests that, when coassembled, they would align head-to-head rather than head-to-tail. This would allow for more plastic functionality of the intermediate filament network. |
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The amount of GFAP the cell produces is regulated by numerous methods, such as [[cytokine]] and [[hormone]] presence. Increased expression of this protein is evident in different situations, commonly referred to as "[[astrocyte|Astrocytic]] activation". During development, vimentin, another type III intermediate filament, is colocalized with GFAP in immature glial cells, as well as glioma (tumor) cell lines, but not in mature astroctyes.<ref name="r3"/> This could indicate, due to the proposed head-to-head structure, that GFAP and vimentin filaments serve a very different purpose than each serves individually. |
The amount of GFAP the cell produces is regulated by numerous methods, such as [[cytokine]] and [[hormone]] presence. Increased expression of this protein is evident in different situations, commonly referred to as "[[astrocyte|Astrocytic]] activation". During development, vimentin, another type III intermediate filament, is colocalized with GFAP in immature glial cells, as well as glioma (tumor) cell lines, but not in mature astroctyes.<ref name="r3"/> This could indicate, due to the proposed head-to-head structure, that GFAP and vimentin filaments serve a very different purpose than each serves individually. |
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In mature cells, the most studied avenue of change in filament amount is the [[phosphorylation]] of GFAP, which can occur at five different sites on the protein.<ref name=" |
In mature cells, the most studied avenue of change in filament amount is the [[phosphorylation]] of GFAP, which can occur at five different sites on the protein.<ref name="pmid2155236">{{cite journal | author = Inagaki M, Gonda Y, Nishizawa K, Kitamura S, Sato C, Ando S, Tanabe K, Kikuchi K, Tsuiki S, Nishi Y | title = Phosphorylation sites linked to glial filament disassembly in vitro locate in a non-alpha-helical head domain | journal = J. Biol. Chem. | volume = 265 | issue = 8 | pages = 4722–9 | year = 1990 | pmid = 2155236 | doi = | issn = | url = http://www.jbc.org/cgi/content/abstract/265/8/4722 }}</ref> This post-translational modification occurs at the head domain and alters the charge of the protein, resulting in disaggregation and subsequent break down of the filaments. The relationship between the level of filamentous GFAP present is usually in a stable equilibrium with free protein, and currently the functional importance of the alteration in the levels of GFAP is not fully understood. |
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==Cellular function== |
==Cellular function== |
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GFAP is expressed in the [[central nervous system]] in astrocyte cells. It is involved in many cellular functioning processes, such as cell structure and movement, cell communication, and the functioning of the [[blood brain barrier]]. |
GFAP is expressed in the [[central nervous system]] in astrocyte cells. It is involved in many cellular functioning processes, such as cell structure and movement, cell communication, and the functioning of the [[blood brain barrier]]. |
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GFAP has been shown to play a role in [[mitosis]] by adjusting the filament network present in the cell. During mitosis, there is an increase in the amount of phosphorylated GFAP, and a movement of this modified protein to the cleavage furrow.<ref name=" |
GFAP has been shown to play a role in [[mitosis]] by adjusting the filament network present in the cell. During mitosis, there is an increase in the amount of phosphorylated GFAP, and a movement of this modified protein to the cleavage furrow.<ref name="pmid2165732">{{cite journal | author = Tardy M, Fages C, Le Prince G, Rolland B, Nunez J | title = Regulation of the glial fibrillary acidic protein (GFAP) and of its encoding mRNA in the developing brain and in cultured astrocytes | journal = Adv. Exp. Med. Biol. | volume = 265 | issue = | pages = 41–52 | year = 1990 | pmid = 2165732 | doi = | issn = }}</ref> There are different sets of kinases at work; [[cdc2]] [[kinase]] acts only at the [[G2 phase]] transition, while other GFAP kinases are active at the cleavage furrow alone. This specificity of location allows for precise regulation of GFAP distribution to the daughter cells. |
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In mature cells, many GFAP functions have been discovered using GFAP [[knockout mice]]. These [[knockout mice]] lack intermediate filaments in the [[hippocampus]] and in the [[white matter]] of the spinal cord. Research also shows that in older mice there is a degeneration of multiple astrocyte functions; the myelination becomes abnormal, white matter structure deteriorates, and there are noticeable changes to the [[blood-brain barrier]].<ref name=" |
In mature cells, many GFAP functions have been discovered using GFAP [[knockout mice]]. These [[knockout mice]] lack intermediate filaments in the [[hippocampus]] and in the [[white matter]] of the spinal cord. Research also shows that in older mice there is a degeneration of multiple astrocyte functions; the myelination becomes abnormal, white matter structure deteriorates, and there are noticeable changes to the [[blood-brain barrier]].<ref name="pmid2052130">{{cite journal | author = Goss JR, Finch CE, Morgan DG | title = Age-related changes in glial fibrillary acidic protein mRNA in the mouse brain | journal = Neurobiol. Aging | volume = 12 | issue = 2 | pages = 165–70 | year = 1991 | pmid = 2052130 | doi = | issn = }}</ref> Therefore, GFAP is believed to be involved in the long term upkeep of normal CNS myelination. |
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GFAP is also proposed to play a role in astrocyte-neuron interactions. In vitro, using [[antisense RNA]], astrocytes lacking GFAP do not form the extensions usually present with neurons. Research also shows that [[Purkinje cells]] in GFAP knockout mice do not exhibit normal structure, and these mice have deficits in some conditioning experiments, such as eye-blink tasks.<ref name="r7">OMIM: 137780. Glial Fibrillary Acidic Protein, GFAP. |
GFAP is also proposed to play a role in astrocyte-neuron interactions. In vitro, using [[antisense RNA]], astrocytes lacking GFAP do not form the extensions usually present with neurons. Research also shows that [[Purkinje cells]] in GFAP knockout mice do not exhibit normal structure, and these mice have deficits in some conditioning experiments, such as eye-blink tasks.<ref name="r7">OMIM: 137780. Glial Fibrillary Acidic Protein, GFAP. |
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==References== |
==References== |
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Revision as of 13:47, 25 November 2007
Glial fibrillary acidic protein (GFAP) is an intermediate filament (IF) protein that is found in glial cells such as astrocytes. First described in 1971,[5] GFAP is a type III IF protein that maps, in humans, to 17q21. It is closely related to its non-epithelial family members, vimentin, desmin, and peripherin, which are all involved in the structure and function of the cell’s cytoskeleton. GFAP helps to maintain astrocyte mechanical strength, as well as the shape of cells.
Structure
Type III intermediate filaments contain three domains, the most conserved of which is the rod domain. The specific DNA sequence for this region of the protein may differ between the different intermediate filament genes for type III proteins, but the structure of the protein is highly conserved. This rod domain coils around that of another filament to form a dimer, with the N-terminal and C-terminal of each filament aligned. Type III filaments such as GFAP are capable of forming both homodimers and heterodimers; GFAP can polymerize with other type III proteins or with neurofilament protein (NF-L).[6] Interestingly, GFAP and other type III IF proteins cannot assemble with keratins, the type I and II intermediate filaments. In cells that express both proteins, two separate intermediate filament networks form, which can allow for specialization and increased variability.
To form networks, the initial dimers combine to make staggered tetramers, which are the basic subunits of an intermediate filament. Since rods alone in vitro do not form filaments, the non-helical domains are necessary for filament formation.[6] The remaining two regions, head and tail, have greater variability of sequence and structure. However, the head of GFAP contains two arginines and an aromatic residue that have been shown to be required for proper assembly.[5] The sizes of the head and tail regions are quite different between GFAP and its more common counterpart vimentin, which suggests that, when coassembled, they would align head-to-head rather than head-to-tail. This would allow for more plastic functionality of the intermediate filament network.
Protein expression
The amount of GFAP the cell produces is regulated by numerous methods, such as cytokine and hormone presence. Increased expression of this protein is evident in different situations, commonly referred to as "Astrocytic activation". During development, vimentin, another type III intermediate filament, is colocalized with GFAP in immature glial cells, as well as glioma (tumor) cell lines, but not in mature astroctyes.[6] This could indicate, due to the proposed head-to-head structure, that GFAP and vimentin filaments serve a very different purpose than each serves individually.
In mature cells, the most studied avenue of change in filament amount is the phosphorylation of GFAP, which can occur at five different sites on the protein.[7] This post-translational modification occurs at the head domain and alters the charge of the protein, resulting in disaggregation and subsequent break down of the filaments. The relationship between the level of filamentous GFAP present is usually in a stable equilibrium with free protein, and currently the functional importance of the alteration in the levels of GFAP is not fully understood.
Cellular function
GFAP is expressed in the central nervous system in astrocyte cells. It is involved in many cellular functioning processes, such as cell structure and movement, cell communication, and the functioning of the blood brain barrier.
GFAP has been shown to play a role in mitosis by adjusting the filament network present in the cell. During mitosis, there is an increase in the amount of phosphorylated GFAP, and a movement of this modified protein to the cleavage furrow.[8] There are different sets of kinases at work; cdc2 kinase acts only at the G2 phase transition, while other GFAP kinases are active at the cleavage furrow alone. This specificity of location allows for precise regulation of GFAP distribution to the daughter cells. In mature cells, many GFAP functions have been discovered using GFAP knockout mice. These knockout mice lack intermediate filaments in the hippocampus and in the white matter of the spinal cord. Research also shows that in older mice there is a degeneration of multiple astrocyte functions; the myelination becomes abnormal, white matter structure deteriorates, and there are noticeable changes to the blood-brain barrier.[9] Therefore, GFAP is believed to be involved in the long term upkeep of normal CNS myelination.
GFAP is also proposed to play a role in astrocyte-neuron interactions. In vitro, using antisense RNA, astrocytes lacking GFAP do not form the extensions usually present with neurons. Research also shows that Purkinje cells in GFAP knockout mice do not exhibit normal structure, and these mice have deficits in some conditioning experiments, such as eye-blink tasks.[10] Therefore, GFAP is thought to play an important role in the maintenance of Purkinje cell communication, and possibly many other neural cell types.
Disease states
There are multiple disorders associated with improper GFAP regulation, and injury can cause glial cells to react in detrimental ways. Glial scarring is a consequence of several neurodegenerative conditions, as well as injury that severs neural material. The scar is formed by astrocytes interacting with fibrous tissue to re-establish the glia margins around the central tissue core,[11] and is caused by up-regulation of GFAP. The scar acts as a barrier to neuronal growth, and prevents neural regeneration.
Another condition directly related to GFAP is Alexander disease. This disease is a rare genetic disorder, which affects mostly males, that alters the growth of the myelin sheath. Its symptoms include: mental and physical retardation, dementia, enlargement of the brain and head, spasticity (stiffness of arms and/or legs), and seizures.[12] The cellular trait is the presence of cytoplasmic accumulations containing GFAP and heat shock proteins, known as Rosenthal fibers. The relationship between GFAP and Alexander disease is not completely understood, but mutations in the coding region of the GFAP gene are associated with the presence of this condition.[13] These mutations are proposed to act in a gain of function manner, as the knockout GFAP phenotype does not resemble the cytoplasmic GFAP mass. The relationship between the Rosenthal fibers and the observable phenotypes is believed to be due to interference in astrocyte interactions with other cells, and a possible inability to maintain the blood brain barrier.
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000131095 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020932 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b Fuchs E, Weber K (1994). "Intermediate filaments: structure, dynamics, function, and disease". Annu. Rev. Biochem. 63: 345–82. doi:10.1146/annurev.bi.63.070194.002021. PMID 7979242.
- ^ a b c Reeves SA, Helman LJ, Allison A, Israel MA (1989). "Molecular cloning and primary structure of human glial fibrillary acidic protein". Proc. Natl. Acad. Sci. U.S.A. 86 (13): 5178–82. doi:10.1073/pnas.86.13.5178. PMID 2740350.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Inagaki M, Gonda Y, Nishizawa K, Kitamura S, Sato C, Ando S, Tanabe K, Kikuchi K, Tsuiki S, Nishi Y (1990). "Phosphorylation sites linked to glial filament disassembly in vitro locate in a non-alpha-helical head domain". J. Biol. Chem. 265 (8): 4722–9. PMID 2155236.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Tardy M, Fages C, Le Prince G, Rolland B, Nunez J (1990). "Regulation of the glial fibrillary acidic protein (GFAP) and of its encoding mRNA in the developing brain and in cultured astrocytes". Adv. Exp. Med. Biol. 265: 41–52. PMID 2165732.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Goss JR, Finch CE, Morgan DG (1991). "Age-related changes in glial fibrillary acidic protein mRNA in the mouse brain". Neurobiol. Aging. 12 (2): 165–70. PMID 2052130.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ OMIM: 137780. Glial Fibrillary Acidic Protein, GFAP. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=137780
- ^ Liedtke, W., Edelmann, W., Bieri, P., Chiu, F., Cowan, N., Kucherlapati, R., Raine, C. (1996). GFAP Is Necessary for the Integrity of CNS White Matter Architecture and Long-Term Maintenance of Myelination. Neuron 17: 607-615.
- ^ http://healthlink.mcw.edu/article/921383447.html
- ^ Brenner, M., Johnson, A., Boespflug-Tanguy, O. Rodriguez, D., Goldman, J., Messing, A. (2001) Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nature Genet. 27: 117-120