Major vault protein: Difference between revisions
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==The Major Vault Protein== | ==The Major Vault Protein== | ||
<StructureSection load='2qzv' size='340' side='right' caption='The outer shell of the Vault particle' scene=''> | <StructureSection load='2qzv' size='340' side='right' caption='The outer shell of the Vault particle' scene=''> | ||
The Major vault proteins, or MVP, constitute as their name implies most of the mass of the ubiquitous cytosolic ribonuclear particle known as Vault by having 96 copies in each vault particle. Vaults are the largest ribonuclear particles ([[RNP]]) ever described and contain within their barrel-like shape a v[[PARP]] (poly [ADP-ribose] polymerase), TEP1 ([[telomerase]]-associated protein 1) and several short RNAs (vRNA). The outer shell of vaults is mainly comprised of MVP, which weighs 100 kDa, and combined with vRNA, vPARP and TEP1 grant the vault particle it’s 12.9MDa mass and 41 X 41 X 71.5 nm size. MVP is expressed in many cells, but it is most abundant in [[dendritic]] cells and [[macrophage]]s. Though having been discovered over 20 years ago, MVP specific function is still in controversy, but evidence have been gathered that might indicating its importance in intracellular signal transduction, cell apoptosis, drug resistance and the immune system. | The Major vault proteins, or MVP, constitute as their name implies most of the mass of the ubiquitous cytosolic ribonuclear particle known as Vault by having 96 copies in each vault particle. Vaults are the largest ribonuclear particles ([[RNP]]) ever described and contain within their barrel-like shape a v[[PARP]] (poly [ADP-ribose] polymerase), TEP1 ([[telomerase]]-associated protein 1) and several short RNAs (vRNA). The outer shell of vaults is mainly comprised of MVP, which weighs 100 kDa, and combined with vRNA, vPARP and TEP1 grant the vault particle it’s 12.9MDa mass and 41 X 41 X 71.5 nm size. MVP is expressed in many cells, but it is most abundant in [[dendritic]] cells and [[macrophage]]s. Though having been discovered over 20 years ago, MVP specific function is still in controversy, but evidence have been gathered that might indicating its importance in intracellular signal transduction, cell apoptosis, drug resistance and the immune system <ref> Berger, W., Steiner, E., Grusch, M., Elbling, L., & Micksche, M. (2009). Vaults and the major vault protein: novel roles in signal pathway regulation and immunity. Cellular and molecular life sciences, 66(1), 43. </ref>. | ||
== Function and relevance == | == Function and relevance == | ||
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Zimmermann, H. (1996) The major vault protein (MVP100) is | Zimmermann, H. (1996) The major vault protein (MVP100) is | ||
contained in cholinergic nerve terminals of electric ray | contained in cholinergic nerve terminals of electric ray | ||
electric organ. J. Biol. Chem. 271, 13908 – 13915. </ref> <ref> Kowalski, M. P., Dubouix-Bourandy, A., Bajmoczi, M., | electric organ. J. Biol. Chem. 271, 13908 – 13915. </ref> <ref name=kow> Kowalski, M. P., Dubouix-Bourandy, A., Bajmoczi, M., | ||
Golan, D. E., Zaidi, T., Coutinho-Sledge, Y. S., Gygi, M. P., | Golan, D. E., Zaidi, T., Coutinho-Sledge, Y. S., Gygi, M. P., | ||
Gygi, S. P., Wiemer, E. A., and Pier, G. B. (2007) Host | Gygi, S. P., Wiemer, E. A., and Pier, G. B. (2007) Host | ||
resistance to lung infection mediated by major vault protein in | resistance to lung infection mediated by major vault protein in | ||
epithelial cells. Science 317, 130 – 132.</ref> and in vitro and clinical correlation with drug resistance <ref> Steiner, E., Holzmann, K., Elbling, L., Micksche, M., and | epithelial cells. Science 317, 130 – 132.</ref> and in vitro and clinical correlation with drug resistance <ref name=stein> Steiner, E., Holzmann, K., Elbling, L., Micksche, M., and | ||
Berger, W. (2006) Cellular functions of vaults and their | Berger, W. (2006) Cellular functions of vaults and their | ||
involvement in multidrug resistance. Curr. Drug Targets 7, | involvement in multidrug resistance. Curr. Drug Targets 7, | ||
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major vault protein in epidermal growth factor-dependent cell | major vault protein in epidermal growth factor-dependent cell | ||
signalling. Febs J. 273, 793 – 804.</ref>. This data is thought to indicate that MVP might have a scaffolding function for signal transduction.<ref name=kolli /> | signalling. Febs J. 273, 793 – 804.</ref>. This data is thought to indicate that MVP might have a scaffolding function for signal transduction.<ref name=kolli /> | ||
* MVP, together with the vRNA of vaults, were found to bind to [[Estrogen]] receptors by interacting through several proto-NLS found on the receptors and which are in charge of the hormone-independent nuclear import | * MVP, together with the vRNA of vaults, were found to bind to [[Estrogen]] receptors by interacting through several proto-NLS found on the receptors and which are in charge of the hormone-independent nuclear import <ref> Ylikomi, T., Bocquel, M. T., Berry, M., Gronemeyer, H., and | ||
* MVP (-/-) mice are extremely prone to pseudomonas aeruginosa infections, thus it is speculated that MVP is involved in the signal transduction activating the innate-immune system to some extent | Chambon, P. (1992) Cooperation of proto-signals for nuclear | ||
accumulation of estrogen and progesterone receptors. Embo. | |||
J. 11, 3681 – 3694. </ref>. | |||
* MVP (-/-) mice are extremely prone to pseudomonas aeruginosa infections, thus it is speculated that MVP is involved in the signal transduction activating the innate-immune system to some extent<ref name=kow />. | |||
== Structural highlights == | == Structural highlights == | ||
MVP is highly conserved in evolution and can create the entire outer shell of the vault barrel structure, which is comprised of two identical halves. The outer shell is a closed, smooth surface without any large gaps or windows. When considering the individual MVP within a vault particle, their <scene name='78/783129/N-terminus/1'>N-terminus ( residues 113–620)</scene> forms the waist of the particle while their <scene name='78/783129/C-terminus/2'>C-terminus (residues 621-893)</scene> builds the cap and the cap/barrel junction[26]. This leads to the current belief that the N-terminus accounts for the non-covalent interactions between the identical particle halves <ref name=Mikyas> Mikyas, Y., Makabi, M., Raval-Fernandes, S., Harrington, L., Kickhoefer, V. A., Rome, L. H., and Stewart, P. L. (2004) Cryoelectron microscopy imaging of recombinant and tissue derived vaults: localization of the MVP N termini and VPARP. J. Mol. Biol. 344, 91 – 105. </ref>. In addition, the individual MVP represents a unique protein that does not share a homology with other proteins, yet exhibits a high degree of conservation <ref name=kong /> <ref name=Mikyas /> <ref> Kickhoefer, V. A., Vasu, S. K., and Rome, L. H. (1996) Vaults | MVP is highly conserved in evolution and can create the entire outer shell of the vault barrel structure, which is comprised of two identical halves. The outer shell is a closed, smooth surface without any large gaps or windows. When considering the individual MVP within a vault particle, their <scene name='78/783129/N-terminus/1'>N-terminus ( residues 113–620)</scene> forms the waist of the particle while their <scene name='78/783129/C-terminus/2'>C-terminus (residues 621-893)</scene> builds the cap and the cap/barrel junction[26]. This leads to the current belief that the N-terminus accounts for the non-covalent interactions between the identical particle halves <ref name=Mikyas> Mikyas, Y., Makabi, M., Raval-Fernandes, S., Harrington, L., Kickhoefer, V. A., Rome, L. H., and Stewart, P. L. (2004) Cryoelectron microscopy imaging of recombinant and tissue derived vaults: localization of the MVP N termini and VPARP. J. Mol. Biol. 344, 91 – 105. </ref>. In addition, the individual MVP represents a unique protein that does not share a homology with other proteins, yet exhibits a high degree of conservation <ref name=kong /> <ref name=Mikyas /> <ref name=kick> Kickhoefer, V. A., Vasu, S. K., and Rome, L. H. (1996) Vaults | ||
are the answer, what is the question? Trends Cell Biol. 6, 174 – 178 | are the answer, what is the question? Trends Cell Biol. 6, 174 – 178.</ref> - around 90% within mammals <ref name=kesh> Kedersha, N. L., Miquel, M. C., Bittner, D., and Rome, L. H. (1990) Vaults. II. Ribonucleoprotein structures are highly conserved among higher and lower eukaryotes. J. Cell Biol. 110, 895 – 901. </ref> <ref name=mossink> Mossink, M. H., van Zon, A., Scheper, R. J.,Sonneveld, P., Wiemer, E. A., Schoester, M., Houtsmuller, A. B., Scheffer, G. L., Franzel-Luiten, E., Kickhoefer, V. A., Mossink, M., Poderycki, M. J., Chan, E. K., and Rome, L. H. (2003) Vaults: a ribonucleoprotein particle involved in drug resistance? Oncogene 22, 7458 – 7467.</ref> | ||
There are several domains within MVP, among the most important is the highly conserved<scene name='78/783129/C-terminus/2'> α- helical domain</scene> near the C-terminus that functions as a coiled coil which mediates an interaction between different MVPs and subsequently vault formation. The N-terminal of MVP was reported to bind Ca2+, but while it has been speculated that MVP contains at least two Ca2+-binding [[EF hand]]s in<scene name='78/783129/Ef-hand_location/1'> positions 131–143</scene> <ref> Yu, Z., Fotouhi-Ardakani, N., Wu, L., Maoui, M., Wang, S., Banville, D., and Shen, S. H. (2002) PTEN associates with the vault particles in HeLa cells. J. Biol. Chem. 277, 40247 – 40252. </ref> , substructure determinations by NMR could not confirm these EF hands and thus an alternative Ca2+ mechanism was suggested which included coordination by large number of <scene name='78/783129/Beta_loops/1'>acidic residues in the long β1/β2 and β2/β3 loops</scene> (Figure 1) of multiple MVP domains <ref> Kozlov, G., Vavelyuk, O., Minailiuc, O., Banville, D., Gehring, K., and Ekiel, I. (2006) Solution structure of a two-repeat fragment of major vault protein. J. Mol. Biol. 356, 444 – 452 </ref> , in a way similar to that found in[[ integrin]]s. | |||
There are several domains within MVP, among the most important is the highly conserved<scene name='78/783129/C-terminus/2'> α- helical domain</scene> near the C-terminus that functions as a coiled coil which mediates an interaction between different MVPs and subsequently vault formation. The N-terminal of MVP was reported to bind Ca2+, but while it has been speculated that MVP contains at least two Ca2+-binding [[EF hand]]s in<scene name='78/783129/Ef-hand_location/1'> positions 131–143</scene> <ref> Yu, Z., Fotouhi-Ardakani, N., Wu, L., Maoui, M., Wang, S., Banville, D., and Shen, S. H. (2002) PTEN associates with the vault particles in HeLa cells. J. Biol. Chem. 277, 40247 – 40252. </ref> , substructure determinations by NMR could not confirm these EF hands and thus an alternative Ca2+ mechanism was suggested which included coordination by large number of <scene name='78/783129/Beta_loops/1'>acidic residues in the long β1/β2 and β2/β3 loops</scene> of multiple MVP domains <ref> Kozlov, G., Vavelyuk, O., Minailiuc, O., Banville, D., Gehring, K., and Ekiel, I. (2006) Solution structure of a two-repeat fragment of major vault protein. J. Mol. Biol. 356, 444 – 452 </ref> , in a way similar to that found in[[ integrin]]s. | |||
==The MVP gene, transcription, translation and post translation modifications== | ==The MVP gene, transcription, translation and post translation modifications== | ||
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H., Rome, L. H., and Scheper, R. J. (1996) Relationship of | H., Rome, L. H., and Scheper, R. J. (1996) Relationship of | ||
LRP-human major vault protein to in vitro and clinical | LRP-human major vault protein to in vitro and clinical | ||
resistance to anticancer drugs. Cytotechnology 19, 191 – 197. </ref> <ref | resistance to anticancer drugs. Cytotechnology 19, 191 – 197. </ref> <ref name=stein /> , malignant transformation <ref name=berger> Berger, W., Spiegl-Kreinecker, S., Buchroithner, J., Elbling, | ||
L., Pirker, C., Fischer, J., and Micksche, M. (2001) Overexpression | L., Pirker, C., Fischer, J., and Micksche, M. (2001) Overexpression | ||
of the human major vault protein in astrocytic | of the human major vault protein in astrocytic | ||
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==Vault particles and MVP dynamics and localizations== | ==Vault particles and MVP dynamics and localizations== | ||
Vaults have been shown to occasionally open up into a flower-like structure with 8 petals (figure | Vaults have been shown to occasionally open up into a flower-like structure with 8 petals (figure 2) <ref name=kick />, and that it is possible to exchange the particles that vaults are comprised from, MVP included. This means that the outer shell, which is mainly MVP, is not static but allows some degree of dynamics. | ||
Vaults, meaning MVP, have been shown to localize in different regions within cells. In most studies regarding its location, MVP was found within the cytosol | Vaults, meaning MVP, have been shown to localize in different regions within cells. In most studies regarding its location, MVP was found within the cytosol <ref name=stein /> <ref> van Zon, A., Mossink, M. H., Scheper, R. J., Sonneveld, P., | ||
MVP, as part of the vault particle, was found to be highly dynamic, and also to react to several signals by translocating to a distinct cellular localization such as ruffling edges, neuritic tips and lipids rafts | and Wiemer, E. A. (2003) The vault complex. Cell. Mol. Life | ||
Mammalian vaults, and in extent MVP, were found to predominantly bind to [[tubulin]] di- and oligomers, but some observations have been made suggesting that vault transport is not fully dependent on intact [[microtubule]]s | Sci. 60, 1828 – 1837.</ref>. Despite this, other groups have found MVP to interact with the [[nuclear pore complex]] (NPC) and thus speculate it to be a considerable mass found within them. In other studies MVP was shown to even enter the nucleus <ref name= sles> Slesina, M., Inman, E. M., Rome, L. H., and Volknandt, W. | ||
[[Image:Flower.jpg| thumb | Figure | (2005) Nuclear localization of the major vault protein in U373 | ||
cells. Cell Tissue Res. 321, 97 – 104. </ref>. | |||
MVP, as part of the vault particle, was found to be highly dynamic, and also to react to several signals by translocating to a distinct cellular localization such as ruffling edges, neuritic tips and lipids rafts <ref name=kesh /> <ref name= berger /> <ref name=sles /> <ref name=kow />. | |||
Mammalian vaults, and in extent MVP, were found to predominantly bind to [[tubulin]] di- and oligomers, but some observations have been made suggesting that vault transport is not fully dependent on intact [[microtubule]]s <ref> van Zon, A., Mossink, M. H., Houtsmuller, A. B., Schoester, | |||
M., Scheffer, G. L., Scheper, R. J., Sonneveld, P., and Wiemer, | |||
E. A. (2006) Vault mobility depends in part on microtubules | |||
and vaults can be recruited to the nuclear envelope. Exp. Cell | |||
Res. 312, 245 – 255. </ref>. | |||
[[Image:Flower.jpg| thumb | Figure 2- The closed and open structures of MVP. Taken and modified from: Kickhoefer, V. A., Vasu, S. K., and Rome, L. H. (1996) Vaults | |||
are the answer, what is the question? Trends Cell Biol. 6, 174 – | are the answer, what is the question? Trends Cell Biol. 6, 174 – | ||
178.]] | 178.]] | ||
Revision as of 06:41, 17 March 2018
The Major Vault Protein
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