Proteopedia - User contributions [en]

Major vault protein

2018-03-17T06:57:56Z

Idan Ben-Nachum:

==The Major Vault Protein==
<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 <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 ==
Though extremely ubiquitous, there is still controversy regarding MVP’s specific function, but all the same some hypotheses regarding MVP’s main role relies on their barrel-like shape due to the assumption that “form ever follows function”<ref> Suprenant, K. A. (2002) Vault ribonucleoprotein particles:
sarcophagi, gondolas, or safety deposit boxes? Biochemistry
41, 14447 – 14454</ref>. In addition, there are growing evidence regarding several aspects MVP might be relevant in:
===MVP and drug resistance===
MVP is thought to be identical to the human lung resistance protein (LRP) that is overexpressed in multiple chemotherapy resistance models <ref> Izquierdo, M. A., Scheffer, G. L., Flens, M. J., Shoemaker, R.
H., Rome, L. H., and Scheper, R. J. (1996) Relationship of
LRP-human major vault protein to in vitro and clinical
resistance to anticancer drugs. Cytotechnology 19, 191 – 197.</ref>. Though MVP is also overexpressed in drug resistant human cancer cells, its role in drug resistance has some contradictory observations: While on the one hand knockdown of MVP by siRNA has led to accumulation of drugs like doxorubicin, MVP(-/-) mice did not exhibited any hypersensitivity to drugs <ref> Mossink, M. H., van Zon, A., Franzel-Luiten, E., Schoester,M., Kickhoefer, V. A., Scheffer, G. L., Scheper, R. J.,Sonneveld, P., and Wiemer, E. A. (2002) Disruption of themurine major vault protein (MVP/LRP) gene does not induce hypersensitivity to cytostatics. Cancer Res. 62, 7298 – 7304. </ref>.
===MVP and apoptosis===
MVP was found to enhance the expression of the anti-apoptotic protein [[bcl-2]] in senescent human fibroblasts <ref> Ryu, S. J., An, H. J., Oh, Y. S., Choi, H. R., Ha, M. K., and Park, S. C. (2008) On the role of major vault protein in the resistance of senescent human diploid fibroblasts to apoptosis. Cell Death Differ. doi: 10.1038/cdd.2008.96.</ref>. By binding to [[COP1]], which is an [[E3 ligase]], MVP forms an interaction which is essential for the degradation of [[c-June]]. This degradation is important in senescent human fibroblasts regarding the modulation of the anti-apoptotic protein bcl-2, and it is reduced when MVP is subjected to UV light which causes it to be tyrosine-phosphorylated.
===MVP and vaults in signal regulation and transport platforms===
Though the inner cavity of the vault particle created by MVP was reported to accommodate an unknown inner mass <ref name=kong> Kong, L. B., Siva, A. C., Rome, L. H., and Stewart, P. L. (1999)
Structure of the vault, a ubiquitous celular component.
Structure Fold Des. 7, 371 – 379.</ref>, and though vaults have known qualities like rapid movement to [[lipid raft]]s, unique subcellular localization <ref> Slesina, M., Inman, E. M., Rome, L. H., and Volknandt, W.
(2005) Nuclear localization of the major vault protein in U373
cells. Cell Tissue Res. 321, 97 – 104.</ref> <ref> Herrmann, C., Golkaramnay, E., Inman, E., Rome, L., and
Volknandt, W. (1999) Recombinant major vault protein is
targeted to neuritic tips of PC12 cells. J. Cell Biol. 144, 1163 –
1172.</ref> <ref> Herrmann, C., Volknandt, W., Wittich, B., Kellner, R., and
Zimmermann, H. (1996) The major vault protein (MVP100) is
contained in cholinergic nerve terminals of electric ray
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.,
Gygi, S. P., Wiemer, E. A., and Pier, G. B. (2007) Host
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 name=stein> Steiner, E., Holzmann, K., Elbling, L., Micksche, M., and
Berger, W. (2006) Cellular functions of vaults and their
involvement in multidrug resistance. Curr. Drug Targets 7,
923 – 934. </ref> (that led some to hypothesize that MVP is a promiscuous transport vehicle), no consensus has been reached regarding MVP’s role in intracellular transport. Still, there are some known relations between MVP and signal transduction proteins:
* MVP binds to and is thought to help translocate [[PTEN]] through the [[NPC]]. PTEN is important in inhibiting the [[PI3K]]/[[AKT]] pathway which inhibits [[MAPK]] in the nucleus. This way, MVP is thought to reduce expression of [[cyclin D]] and in turn cause G0/G1 arrest<ref> Chung, J. H., and Eng, C. (2005) Nuclear-cytoplasmic
partitioning of phosphatase and tensin homologue deleted
on chromosome 10 (PTEN) differentially regulates the cell
cycle and apoptosis. Cancer Res. 65, 8096 – 8100</ref>.
* MVP is phosphorylated due to [[EGFR]] stimulation on tyrosine residues<ref> Yi, C., Li, S., Chen, X., Wiemer, E. A., Wang, J., Wei, N., and
Deng, X. W. (2005) Major vault protein, in concert with
constitutively photomorphogenic 1, negatively regulates cJun-mediated
activator protein 1 transcription in mammalian
cells. Cancer Res. 65, 5835 – 5840.</ref>, thus allowing it to bind to the MAPK [[Erk]] and the tyrosine phosphorylase [[SHP-2]]<ref name=kolli> Kolli, S., Zito, C. I., Mossink, M. H., Wiemer, E. A., and
Bennett, A. M. (2004) The major vault protein is a novel
substrate for the tyrosine phosphatase SHP-2 and scaffold
protein in epidermal growth factor signaling. J. Biol.
Chem. 279, 29374 – 29385. </ref>. Since the interaction between SHP-2 and MVP is achieved through [[SH2 domain]], it is not surprising that the [[Src]] protein was found to bind MVP as well <ref> Kim, E., Lee, S., Mian, M. F., Yun, S. U., Song, M., Yi, K. S.,
Ryu, S. H., and Suh, P. G. (2006) Crosstalk between Src and
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 />
* 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
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 ==
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.</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.

[[Image:Pdbnmr.jpg | thumb | '''Figure 1-''' The structure of the two domain fragment of MVP, depicted by NMR. Taken from the [[1y7x]] entry in the PBD. credit to: 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.]]

==The MVP gene, transcription, translation and post translation modifications==
The human MVP gene resides on chromosome 16p11.2. Upregulation of MVP can be caused by chemotherapy resistance <ref name=mossink /> <ref> Kickhoefer, V. A., Rajavel, K. S., Scheffer, G. L., Dalton, W.
S., Scheper, R. J., and Rome, L. H. (1998) Vaults are upregulated
in multidrug-resistant cancer cell lines. J. Biol.
Chem. 273, 8971 – 8974. </ref> <ref> Izquierdo, M. A., Scheffer, G. L., Flens, M. J., Shoemaker, R.
H., Rome, L. H., and Scheper, R. J. (1996) Relationship of
LRP-human major vault protein to in vitro and clinical
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
of the human major vault protein in astrocytic
brain tumor cells. Int. J. Cancer 94, 377 – 382. </ref>, senescence/aging <ref> Ryu, S. J., An, H. J., Oh, Y. S., Choi, H. R., Ha, M. K., and
Park, S. C. (2008) On the role of major vault protein in the
resistance of senescent human diploid fibroblasts to apoptosis.
Cell Death Differ. doi: 10.1038/cdd.2008.96. </ref> hyperthermia <ref> Stein, U., Jurchott, K., Schlafke, M., and Hohenberger, P.
(2002) Expression of multidrug resistance genes MVP,
MDR1, and MRP1 determined sequentially before, during,
and after hyperthermic isolated limb perfusion of soft tissue
sarcoma and melanoma patients. J. Clin. Oncol. 20, 3282 –
3292. </ref> and estradiol treatment <ref> Abbondanza, C., Rossi, V., Roscigno, A., Gallo, L., Belsito,
A., Piluso, G., Medici, N., Nigro, V., Molinari, A. M.,
Moncharmont, B., and Puca, G. A. (1998) Interaction of
vault particles with estrogen receptor in the MCF-7 breast
cancer cell. J. Cell Biol. 141, 1301 – 1310. </ref>. Other factors that elevate MVP expression are [[cytokine]]s like [[interferons γ]] <ref> Miracco, C., Maellaro, E., Pacenti, L., Del Bello, B.,
Valentini, M. A., Rubegni, P., Pirtoli, L., Volpi, C., Santopietro,
R., and Tosi, P. (2003) Evaluation of MDR1, LRP, MRP,
and topoisomerase IIalpha gene mRNA transcripts before
and after interferon-alpha, and correlation with the mRNA
expression level of the telomerase subunits hTERT and TEP1
in five unselected human melanoma cell lines. Int. J.
Oncol. 23, 213 – 220. </ref> <ref> Steiner, E., Holzmann, K., Pirker, C., Elbling, L., Micksche,
M., Sutterluty, H., and Berger, W. (2006) The major vault
protein is responsive to and interferes with interferongamma-mediated
STAT1 signals. J. Cell Sci. 119, 459 – 469. </ref>, while other like [[TNFα]] suppress it.
The murine and human MVP gene is TATA-less and lacks other core promotor elements. Several of MVP’s transcription factors are involved in cell development and differentiation, but also malignant transformation <ref> Fujii, T., Kawahara, A., Basaki, Y., Hattori, S., Nakashima,
K., Nakano, K., Shirouzu, K., Kohno, K., Yanagawa, T.,
Yamana, H., Nishio, K., Ono, M., Kuwano, M., and Kage, M.
(2008) Expression of HER2 and estrogen receptor alpha
depends upon nuclear localization of Y-box binding protein-1
in human breast cancers. Cancer Res. 68, 1504 – 1512. </ref>.
MVP is postulated to have posttranscriptional regulations, like stabilization of its mRNA <ref> Laurencot, C. M., Scheffer, G. L., Scheper, R. J., and
Shoemaker, R. H. (1997) Increased LRP mRNA expression
is associated with the MDR phenotype in intrinsically
resistant human cancer cell lines. Int. J. Cancer 72, 1021 – 1026. </ref> and alternative splicing in its 5’ UTR which represses its translation <ref> Holzmann, K., Ambrosch, I., Elbling, L., Micksche, M., and
Berger, W. (2001) A small upstream open reading frame
causes inhibition of human major vault protein expression
from a ubiquitous mRNA splice variant. FEBS Lett. 494, 99 –
104. </ref>. MVP degradation is thought to be control by the [[proteasome]] <ref> Sutovsky, P., Manandhar, G., Laurincik, J., Letko, J., Caamano,
J. N., Day, B. N., Lai, L., Prather, R. S., Sharpe-Timms, K.
L., Zimmer, R., and Sutovsky, M. (2005) Expression and
proteasomal degradation of the major vault protein (MVP) in
mammalian oocytes and zygotes. Reproduction 129, 269 – 282. </ref> <ref> Suprenant, K. A., Bloom, N., Fang, J., and Lushington, G.
(2007) The major vault protein is related to the toxic anion
resistance protein (TelA) family. J. Exp. Biol. 210, 946 – 955. </ref> <ref> Yi, C., Li, S., Chen, X., Wiemer, E. A., Wang, J., Wei, N., and
Deng, X. W. (2005) Major vault protein, in concert with
constitutively photomorphogenic 1, negatively regulates cJun-mediated
activator protein 1 transcription in mammalian
cells. Cancer Res. 65, 5835 – 5840 </ref>, but as of today no [[ubiquitin]]ation of vault or MVP has been confirmed.
MVP is subjected to phosphorylation by several proteins such as [[protein kinase C]], [[casein kinase II]] and [[Src kinase]] <ref> Ehrnsperger, C., and Volknandt, W. (2001) Major vault
protein is a substrate of endogenous protein kinases in CHO
and PC12 cells. Biol. Chem. 382, 1463 – 1471. </ref> <ref> Herrmann, C., Kellner, R., and Volknandt, W. (1998) Major
vault protein of electric ray is a phosphoprotein. Neurochem.
Res. 23, 39 – 46. </ref> <ref> Kim, E., Lee, S., Mian, M. F., Yun, S. U., Song, M., Yi, K. S.,
Ryu, S. H., and Suh, P. G. (2006) Crosstalk between Src and
major vault protein in epidermal growth factor-dependent cell
signalling. Febs J. 273, 793 – 804.</ref>, and is believed to be important in signaling regulation. In addition, MVP is subjected to dephosphorylation by SHP-2 <ref> Kolli, S., Zito, C. I., Mossink, M. H., Wiemer, E. A., and
Bennett, A. M. (2004) The major vault protein is a novel
substrate for the tyrosine phosphatase SHP-2 and scaffold
protein in epidermal growth factor signaling. J. Biol.
Chem. 279, 29374 – 29385. </ref> and poly-(ADP)-ribosylation by vPARP <ref> Kickhoefer, V. A., Siva, A. C., Kedersha, N. L., Inman, E. M.,
Ruland, C., Streuli, M., and Rome, L. H. (1999) The 193-kD
vault protein, VPARP, is a novel poly(ADP-ribose) polymerase.
J. Cell Biol. 146, 917 – 928. </ref> , but the impact of these molecular changes are not yet fully known.

==Vault particles and MVP dynamics and localizations==
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 <ref name=stein /> <ref> van Zon, A., Mossink, M. H., Scheper, R. J., Sonneveld, P.,
and Wiemer, E. A. (2003) The vault complex. Cell. Mol. Life
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.
(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 –
178.]]

</StructureSection>
== References ==

<references/>

Major vault protein

2018-03-17T06:56:46Z

Idan Ben-Nachum:

==The Major Vault Protein==
<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 <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 ==
Though extremely ubiquitous, there is still controversy regarding MVP’s specific function, but all the same some hypotheses regarding MVP’s main role relies on their barrel-like shape due to the assumption that “form ever follows function”<ref> Suprenant, K. A. (2002) Vault ribonucleoprotein particles:
sarcophagi, gondolas, or safety deposit boxes? Biochemistry
41, 14447 – 14454</ref>. In addition, there are growing evidence regarding several aspects MVP might be relevant in:
===MVP and drug resistance===
MVP is thought to be identical to the human lung resistance protein (LRP) that is overexpressed in multiple chemotherapy resistance models <ref> Izquierdo, M. A., Scheffer, G. L., Flens, M. J., Shoemaker, R.
H., Rome, L. H., and Scheper, R. J. (1996) Relationship of
LRP-human major vault protein to in vitro and clinical
resistance to anticancer drugs. Cytotechnology 19, 191 – 197.</ref>. Though MVP is also overexpressed in drug resistant human cancer cells, its role in drug resistance has some contradictory observations: While on the one hand knockdown of MVP by siRNA has led to accumulation of drugs like doxorubicin, MVP(-/-) mice did not exhibited any hypersensitivity to drugs <ref> Mossink, M. H., van Zon, A., Franzel-Luiten, E., Schoester,M., Kickhoefer, V. A., Scheffer, G. L., Scheper, R. J.,Sonneveld, P., and Wiemer, E. A. (2002) Disruption of themurine major vault protein (MVP/LRP) gene does not induce hypersensitivity to cytostatics. Cancer Res. 62, 7298 – 7304. </ref>.
===MVP and apoptosis===
MVP was found to enhance the expression of the anti-apoptotic protein [[bcl-2]] in senescent human fibroblasts <ref> Ryu, S. J., An, H. J., Oh, Y. S., Choi, H. R., Ha, M. K., and Park, S. C. (2008) On the role of major vault protein in the resistance of senescent human diploid fibroblasts to apoptosis. Cell Death Differ. doi: 10.1038/cdd.2008.96.</ref>. By binding to [[COP1]], which is an [[E3 ligase]], MVP forms an interaction which is essential for the degradation of [[c-June]]. This degradation is important in senescent human fibroblasts regarding the modulation of the anti-apoptotic protein bcl-2, and it is reduced when MVP is subjected to UV light which causes it to be tyrosine-phosphorylated.
===MVP and vaults in signal regulation and transport platforms===
Though the inner cavity of the vault particle created by MVP was reported to accommodate an unknown inner mass <ref name=kong> Kong, L. B., Siva, A. C., Rome, L. H., and Stewart, P. L. (1999)
Structure of the vault, a ubiquitous celular component.
Structure Fold Des. 7, 371 – 379.</ref>, and though vaults have known qualities like rapid movement to [[lipid raft]]s, unique subcellular localization <ref> Slesina, M., Inman, E. M., Rome, L. H., and Volknandt, W.
(2005) Nuclear localization of the major vault protein in U373
cells. Cell Tissue Res. 321, 97 – 104.</ref> <ref> Herrmann, C., Golkaramnay, E., Inman, E., Rome, L., and
Volknandt, W. (1999) Recombinant major vault protein is
targeted to neuritic tips of PC12 cells. J. Cell Biol. 144, 1163 –
1172.</ref> <ref> Herrmann, C., Volknandt, W., Wittich, B., Kellner, R., and
Zimmermann, H. (1996) The major vault protein (MVP100) is
contained in cholinergic nerve terminals of electric ray
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.,
Gygi, S. P., Wiemer, E. A., and Pier, G. B. (2007) Host
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 name=stein> Steiner, E., Holzmann, K., Elbling, L., Micksche, M., and
Berger, W. (2006) Cellular functions of vaults and their
involvement in multidrug resistance. Curr. Drug Targets 7,
923 – 934. </ref> (that led some to hypothesize that MVP is a promiscuous transport vehicle), no consensus has been reached regarding MVP’s role in intracellular transport. Still, there are some known relations between MVP and signal transduction proteins:
* MVP binds to and is thought to help translocate [[PTEN]] through the [[NPC]]. PTEN is important in inhibiting the [[PI3K]]/[[AKT]] pathway which inhibits [[MAPK]] in the nucleus. This way, MVP is thought to reduce expression of [[cyclin D]] and in turn cause G0/G1 arrest<ref> Chung, J. H., and Eng, C. (2005) Nuclear-cytoplasmic
partitioning of phosphatase and tensin homologue deleted
on chromosome 10 (PTEN) differentially regulates the cell
cycle and apoptosis. Cancer Res. 65, 8096 – 8100</ref>.
* MVP is phosphorylated due to [[EGFR]] stimulation on tyrosine residues<ref> Yi, C., Li, S., Chen, X., Wiemer, E. A., Wang, J., Wei, N., and
Deng, X. W. (2005) Major vault protein, in concert with
constitutively photomorphogenic 1, negatively regulates cJun-mediated
activator protein 1 transcription in mammalian
cells. Cancer Res. 65, 5835 – 5840.</ref>, thus allowing it to bind to the MAPK [[Erk]] and the tyrosine phosphorylase [[SHP-2]]<ref name=kolli> Kolli, S., Zito, C. I., Mossink, M. H., Wiemer, E. A., and
Bennett, A. M. (2004) The major vault protein is a novel
substrate for the tyrosine phosphatase SHP-2 and scaffold
protein in epidermal growth factor signaling. J. Biol.
Chem. 279, 29374 – 29385. </ref>. Since the interaction between SHP-2 and MVP is achieved through [[SH2 domain]], it is not surprising that the [[Src]] protein was found to bind MVP as well <ref> Kim, E., Lee, S., Mian, M. F., Yun, S. U., Song, M., Yi, K. S.,
Ryu, S. H., and Suh, P. G. (2006) Crosstalk between Src and
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 />
* 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
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 ==
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.</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.

[[Image:Pdbnmr.jpg | thumb | '''Figure 1-''' The structure of the two domain fragment of MVP, depicted by NMR. Taken from the [[1Y7X]] entry in the PBD. credit to: 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.]]

==The MVP gene, transcription, translation and post translation modifications==
The human MVP gene resides on chromosome 16p11.2. Upregulation of MVP can be caused by chemotherapy resistance <ref name=mossink /> <ref> Kickhoefer, V. A., Rajavel, K. S., Scheffer, G. L., Dalton, W.
S., Scheper, R. J., and Rome, L. H. (1998) Vaults are upregulated
in multidrug-resistant cancer cell lines. J. Biol.
Chem. 273, 8971 – 8974. </ref> <ref> Izquierdo, M. A., Scheffer, G. L., Flens, M. J., Shoemaker, R.
H., Rome, L. H., and Scheper, R. J. (1996) Relationship of
LRP-human major vault protein to in vitro and clinical
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
of the human major vault protein in astrocytic
brain tumor cells. Int. J. Cancer 94, 377 – 382. </ref>, senescence/aging <ref> Ryu, S. J., An, H. J., Oh, Y. S., Choi, H. R., Ha, M. K., and
Park, S. C. (2008) On the role of major vault protein in the
resistance of senescent human diploid fibroblasts to apoptosis.
Cell Death Differ. doi: 10.1038/cdd.2008.96. </ref> hyperthermia <ref> Stein, U., Jurchott, K., Schlafke, M., and Hohenberger, P.
(2002) Expression of multidrug resistance genes MVP,
MDR1, and MRP1 determined sequentially before, during,
and after hyperthermic isolated limb perfusion of soft tissue
sarcoma and melanoma patients. J. Clin. Oncol. 20, 3282 –
3292. </ref> and estradiol treatment <ref> Abbondanza, C., Rossi, V., Roscigno, A., Gallo, L., Belsito,
A., Piluso, G., Medici, N., Nigro, V., Molinari, A. M.,
Moncharmont, B., and Puca, G. A. (1998) Interaction of
vault particles with estrogen receptor in the MCF-7 breast
cancer cell. J. Cell Biol. 141, 1301 – 1310. </ref>. Other factors that elevate MVP expression are [[cytokine]]s like [[interferons γ]] <ref> Miracco, C., Maellaro, E., Pacenti, L., Del Bello, B.,
Valentini, M. A., Rubegni, P., Pirtoli, L., Volpi, C., Santopietro,
R., and Tosi, P. (2003) Evaluation of MDR1, LRP, MRP,
and topoisomerase IIalpha gene mRNA transcripts before
and after interferon-alpha, and correlation with the mRNA
expression level of the telomerase subunits hTERT and TEP1
in five unselected human melanoma cell lines. Int. J.
Oncol. 23, 213 – 220. </ref> <ref> Steiner, E., Holzmann, K., Pirker, C., Elbling, L., Micksche,
M., Sutterluty, H., and Berger, W. (2006) The major vault
protein is responsive to and interferes with interferongamma-mediated
STAT1 signals. J. Cell Sci. 119, 459 – 469. </ref>, while other like [[TNFα]] suppress it.
The murine and human MVP gene is TATA-less and lacks other core promotor elements. Several of MVP’s transcription factors are involved in cell development and differentiation, but also malignant transformation <ref> Fujii, T., Kawahara, A., Basaki, Y., Hattori, S., Nakashima,
K., Nakano, K., Shirouzu, K., Kohno, K., Yanagawa, T.,
Yamana, H., Nishio, K., Ono, M., Kuwano, M., and Kage, M.
(2008) Expression of HER2 and estrogen receptor alpha
depends upon nuclear localization of Y-box binding protein-1
in human breast cancers. Cancer Res. 68, 1504 – 1512. </ref>.
MVP is postulated to have posttranscriptional regulations, like stabilization of its mRNA <ref> Laurencot, C. M., Scheffer, G. L., Scheper, R. J., and
Shoemaker, R. H. (1997) Increased LRP mRNA expression
is associated with the MDR phenotype in intrinsically
resistant human cancer cell lines. Int. J. Cancer 72, 1021 – 1026. </ref> and alternative splicing in its 5’ UTR which represses its translation <ref> Holzmann, K., Ambrosch, I., Elbling, L., Micksche, M., and
Berger, W. (2001) A small upstream open reading frame
causes inhibition of human major vault protein expression
from a ubiquitous mRNA splice variant. FEBS Lett. 494, 99 –
104. </ref>. MVP degradation is thought to be control by the [[proteasome]] <ref> Sutovsky, P., Manandhar, G., Laurincik, J., Letko, J., Caamano,
J. N., Day, B. N., Lai, L., Prather, R. S., Sharpe-Timms, K.
L., Zimmer, R., and Sutovsky, M. (2005) Expression and
proteasomal degradation of the major vault protein (MVP) in
mammalian oocytes and zygotes. Reproduction 129, 269 – 282. </ref> <ref> Suprenant, K. A., Bloom, N., Fang, J., and Lushington, G.
(2007) The major vault protein is related to the toxic anion
resistance protein (TelA) family. J. Exp. Biol. 210, 946 – 955. </ref> <ref> Yi, C., Li, S., Chen, X., Wiemer, E. A., Wang, J., Wei, N., and
Deng, X. W. (2005) Major vault protein, in concert with
constitutively photomorphogenic 1, negatively regulates cJun-mediated
activator protein 1 transcription in mammalian
cells. Cancer Res. 65, 5835 – 5840 </ref>, but as of today no [[ubiquitin]]ation of vault or MVP has been confirmed.
MVP is subjected to phosphorylation by several proteins such as [[protein kinase C]], [[casein kinase II]] and [[Src kinase]] <ref> Ehrnsperger, C., and Volknandt, W. (2001) Major vault
protein is a substrate of endogenous protein kinases in CHO
and PC12 cells. Biol. Chem. 382, 1463 – 1471. </ref> <ref> Herrmann, C., Kellner, R., and Volknandt, W. (1998) Major
vault protein of electric ray is a phosphoprotein. Neurochem.
Res. 23, 39 – 46. </ref> <ref> Kim, E., Lee, S., Mian, M. F., Yun, S. U., Song, M., Yi, K. S.,
Ryu, S. H., and Suh, P. G. (2006) Crosstalk between Src and
major vault protein in epidermal growth factor-dependent cell
signalling. Febs J. 273, 793 – 804.</ref>, and is believed to be important in signaling regulation. In addition, MVP is subjected to dephosphorylation by SHP-2 <ref> Kolli, S., Zito, C. I., Mossink, M. H., Wiemer, E. A., and
Bennett, A. M. (2004) The major vault protein is a novel
substrate for the tyrosine phosphatase SHP-2 and scaffold
protein in epidermal growth factor signaling. J. Biol.
Chem. 279, 29374 – 29385. </ref> and poly-(ADP)-ribosylation by vPARP <ref> Kickhoefer, V. A., Siva, A. C., Kedersha, N. L., Inman, E. M.,
Ruland, C., Streuli, M., and Rome, L. H. (1999) The 193-kD
vault protein, VPARP, is a novel poly(ADP-ribose) polymerase.
J. Cell Biol. 146, 917 – 928. </ref> , but the impact of these molecular changes are not yet fully known.

==Vault particles and MVP dynamics and localizations==
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 <ref name=stein /> <ref> van Zon, A., Mossink, M. H., Scheper, R. J., Sonneveld, P.,
and Wiemer, E. A. (2003) The vault complex. Cell. Mol. Life
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.
(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 –
178.]]

</StructureSection>
== References ==

<references/>

Major vault protein

2018-03-17T06:52:43Z

Idan Ben-Nachum:

==The Major Vault Protein==
<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 <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 ==
Though extremely ubiquitous, there is still controversy regarding MVP’s specific function, but all the same some hypotheses regarding MVP’s main role relies on their barrel-like shape due to the assumption that “form ever follows function”<ref> Suprenant, K. A. (2002) Vault ribonucleoprotein particles:
sarcophagi, gondolas, or safety deposit boxes? Biochemistry
41, 14447 – 14454</ref>. In addition, there are growing evidence regarding several aspects MVP might be relevant in:
===MVP and drug resistance===
MVP is thought to be identical to the human lung resistance protein (LRP) that is overexpressed in multiple chemotherapy resistance models <ref> Izquierdo, M. A., Scheffer, G. L., Flens, M. J., Shoemaker, R.
H., Rome, L. H., and Scheper, R. J. (1996) Relationship of
LRP-human major vault protein to in vitro and clinical
resistance to anticancer drugs. Cytotechnology 19, 191 – 197.</ref>. Though MVP is also overexpressed in drug resistant human cancer cells, its role in drug resistance has some contradictory observations: While on the one hand knockdown of MVP by siRNA has led to accumulation of drugs like doxorubicin, MVP(-/-) mice did not exhibited any hypersensitivity to drugs <ref> Mossink, M. H., van Zon, A., Franzel-Luiten, E., Schoester,M., Kickhoefer, V. A., Scheffer, G. L., Scheper, R. J.,Sonneveld, P., and Wiemer, E. A. (2002) Disruption of themurine major vault protein (MVP/LRP) gene does not induce hypersensitivity to cytostatics. Cancer Res. 62, 7298 – 7304. </ref>.
===MVP and apoptosis===
MVP was found to enhance the expression of the anti-apoptotic protein [[bcl-2]] in senescent human fibroblasts <ref> Ryu, S. J., An, H. J., Oh, Y. S., Choi, H. R., Ha, M. K., and Park, S. C. (2008) On the role of major vault protein in the resistance of senescent human diploid fibroblasts to apoptosis. Cell Death Differ. doi: 10.1038/cdd.2008.96.</ref>. By binding to [[COP1]], which is an [[E3 ligase]], MVP forms an interaction which is essential for the degradation of [[c-June]]. This degradation is important in senescent human fibroblasts regarding the modulation of the anti-apoptotic protein bcl-2, and it is reduced when MVP is subjected to UV light which causes it to be tyrosine-phosphorylated.
===MVP and vaults in signal regulation and transport platforms===
Though the inner cavity of the vault particle created by MVP was reported to accommodate an unknown inner mass <ref name=kong> Kong, L. B., Siva, A. C., Rome, L. H., and Stewart, P. L. (1999)
Structure of the vault, a ubiquitous celular component.
Structure Fold Des. 7, 371 – 379.</ref>, and though vaults have known qualities like rapid movement to [[lipid raft]]s, unique subcellular localization <ref> Slesina, M., Inman, E. M., Rome, L. H., and Volknandt, W.
(2005) Nuclear localization of the major vault protein in U373
cells. Cell Tissue Res. 321, 97 – 104.</ref> <ref> Herrmann, C., Golkaramnay, E., Inman, E., Rome, L., and
Volknandt, W. (1999) Recombinant major vault protein is
targeted to neuritic tips of PC12 cells. J. Cell Biol. 144, 1163 –
1172.</ref> <ref> Herrmann, C., Volknandt, W., Wittich, B., Kellner, R., and
Zimmermann, H. (1996) The major vault protein (MVP100) is
contained in cholinergic nerve terminals of electric ray
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.,
Gygi, S. P., Wiemer, E. A., and Pier, G. B. (2007) Host
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 name=stein> Steiner, E., Holzmann, K., Elbling, L., Micksche, M., and
Berger, W. (2006) Cellular functions of vaults and their
involvement in multidrug resistance. Curr. Drug Targets 7,
923 – 934. </ref> (that led some to hypothesize that MVP is a promiscuous transport vehicle), no consensus has been reached regarding MVP’s role in intracellular transport. Still, there are some known relations between MVP and signal transduction proteins:
* MVP binds to and is thought to help translocate [[PTEN]] through the [[NPC]]. PTEN is important in inhibiting the [[PI3K]]/[[AKT]] pathway which inhibits [[MAPK]] in the nucleus. This way, MVP is thought to reduce expression of [[cyclin D]] and in turn cause G0/G1 arrest<ref> Chung, J. H., and Eng, C. (2005) Nuclear-cytoplasmic
partitioning of phosphatase and tensin homologue deleted
on chromosome 10 (PTEN) differentially regulates the cell
cycle and apoptosis. Cancer Res. 65, 8096 – 8100</ref>.
* MVP is phosphorylated due to [[EGFR]] stimulation on tyrosine residues<ref> Yi, C., Li, S., Chen, X., Wiemer, E. A., Wang, J., Wei, N., and
Deng, X. W. (2005) Major vault protein, in concert with
constitutively photomorphogenic 1, negatively regulates cJun-mediated
activator protein 1 transcription in mammalian
cells. Cancer Res. 65, 5835 – 5840.</ref>, thus allowing it to bind to the MAPK [[Erk]] and the tyrosine phosphorylase [[SHP-2]]<ref name=kolli> Kolli, S., Zito, C. I., Mossink, M. H., Wiemer, E. A., and
Bennett, A. M. (2004) The major vault protein is a novel
substrate for the tyrosine phosphatase SHP-2 and scaffold
protein in epidermal growth factor signaling. J. Biol.
Chem. 279, 29374 – 29385. </ref>. Since the interaction between SHP-2 and MVP is achieved through [[SH2 domain]], it is not surprising that the [[Src]] protein was found to bind MVP as well <ref> Kim, E., Lee, S., Mian, M. F., Yun, S. U., Song, M., Yi, K. S.,
Ryu, S. H., and Suh, P. G. (2006) Crosstalk between Src and
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 />
* 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
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 ==
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.</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.

[[Image:Pdbnmr.jpg | thumb | '''Figure 1-''' The structure of the two domain fragment of MVP, depicted by NMR. Taken from the 1Y7X entry in the PBD. credit to: 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.]]

==The MVP gene, transcription, translation and post translation modifications==
The human MVP gene resides on chromosome 16p11.2. Upregulation of MVP can be caused by chemotherapy resistance <ref name=mossink /> <ref> Kickhoefer, V. A., Rajavel, K. S., Scheffer, G. L., Dalton, W.
S., Scheper, R. J., and Rome, L. H. (1998) Vaults are upregulated
in multidrug-resistant cancer cell lines. J. Biol.
Chem. 273, 8971 – 8974. </ref> <ref> Izquierdo, M. A., Scheffer, G. L., Flens, M. J., Shoemaker, R.
H., Rome, L. H., and Scheper, R. J. (1996) Relationship of
LRP-human major vault protein to in vitro and clinical
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
of the human major vault protein in astrocytic
brain tumor cells. Int. J. Cancer 94, 377 – 382. </ref>, senescence/aging <ref> Ryu, S. J., An, H. J., Oh, Y. S., Choi, H. R., Ha, M. K., and
Park, S. C. (2008) On the role of major vault protein in the
resistance of senescent human diploid fibroblasts to apoptosis.
Cell Death Differ. doi: 10.1038/cdd.2008.96. </ref> hyperthermia <ref> Stein, U., Jurchott, K., Schlafke, M., and Hohenberger, P.
(2002) Expression of multidrug resistance genes MVP,
MDR1, and MRP1 determined sequentially before, during,
and after hyperthermic isolated limb perfusion of soft tissue
sarcoma and melanoma patients. J. Clin. Oncol. 20, 3282 –
3292. </ref> and estradiol treatment <ref> Abbondanza, C., Rossi, V., Roscigno, A., Gallo, L., Belsito,
A., Piluso, G., Medici, N., Nigro, V., Molinari, A. M.,
Moncharmont, B., and Puca, G. A. (1998) Interaction of
vault particles with estrogen receptor in the MCF-7 breast
cancer cell. J. Cell Biol. 141, 1301 – 1310. </ref>. Other factors that elevate MVP expression are [[cytokine]]s like [[interferons γ]] <ref> Miracco, C., Maellaro, E., Pacenti, L., Del Bello, B.,
Valentini, M. A., Rubegni, P., Pirtoli, L., Volpi, C., Santopietro,
R., and Tosi, P. (2003) Evaluation of MDR1, LRP, MRP,
and topoisomerase IIalpha gene mRNA transcripts before
and after interferon-alpha, and correlation with the mRNA
expression level of the telomerase subunits hTERT and TEP1
in five unselected human melanoma cell lines. Int. J.
Oncol. 23, 213 – 220. </ref> <ref> Steiner, E., Holzmann, K., Pirker, C., Elbling, L., Micksche,
M., Sutterluty, H., and Berger, W. (2006) The major vault
protein is responsive to and interferes with interferongamma-mediated
STAT1 signals. J. Cell Sci. 119, 459 – 469. </ref>, while other like [[TNFα]] suppress it.
The murine and human MVP gene is TATA-less and lacks other core promotor elements. Several of MVP’s transcription factors are involved in cell development and differentiation, but also malignant transformation <ref> Fujii, T., Kawahara, A., Basaki, Y., Hattori, S., Nakashima,
K., Nakano, K., Shirouzu, K., Kohno, K., Yanagawa, T.,
Yamana, H., Nishio, K., Ono, M., Kuwano, M., and Kage, M.
(2008) Expression of HER2 and estrogen receptor alpha
depends upon nuclear localization of Y-box binding protein-1
in human breast cancers. Cancer Res. 68, 1504 – 1512. </ref>.
MVP is postulated to have posttranscriptional regulations, like stabilization of its mRNA <ref> Laurencot, C. M., Scheffer, G. L., Scheper, R. J., and
Shoemaker, R. H. (1997) Increased LRP mRNA expression
is associated with the MDR phenotype in intrinsically
resistant human cancer cell lines. Int. J. Cancer 72, 1021 – 1026. </ref> and alternative splicing in its 5’ UTR which represses its translation <ref> Holzmann, K., Ambrosch, I., Elbling, L., Micksche, M., and
Berger, W. (2001) A small upstream open reading frame
causes inhibition of human major vault protein expression
from a ubiquitous mRNA splice variant. FEBS Lett. 494, 99 –
104. </ref>. MVP degradation is thought to be control by the [[proteasome]] <ref> Sutovsky, P., Manandhar, G., Laurincik, J., Letko, J., Caamano,
J. N., Day, B. N., Lai, L., Prather, R. S., Sharpe-Timms, K.
L., Zimmer, R., and Sutovsky, M. (2005) Expression and
proteasomal degradation of the major vault protein (MVP) in
mammalian oocytes and zygotes. Reproduction 129, 269 – 282. </ref> <ref> Suprenant, K. A., Bloom, N., Fang, J., and Lushington, G.
(2007) The major vault protein is related to the toxic anion
resistance protein (TelA) family. J. Exp. Biol. 210, 946 – 955. </ref> <ref> Yi, C., Li, S., Chen, X., Wiemer, E. A., Wang, J., Wei, N., and
Deng, X. W. (2005) Major vault protein, in concert with
constitutively photomorphogenic 1, negatively regulates cJun-mediated
activator protein 1 transcription in mammalian
cells. Cancer Res. 65, 5835 – 5840 </ref>, but as of today no [[ubiquitin]]ation of vault or MVP has been confirmed.
MVP is subjected to phosphorylation by several proteins such as [[protein kinase C]], [[casein kinase II]] and [[Src kinase]] <ref> Ehrnsperger, C., and Volknandt, W. (2001) Major vault
protein is a substrate of endogenous protein kinases in CHO
and PC12 cells. Biol. Chem. 382, 1463 – 1471. </ref> <ref> Herrmann, C., Kellner, R., and Volknandt, W. (1998) Major
vault protein of electric ray is a phosphoprotein. Neurochem.
Res. 23, 39 – 46. </ref> <ref> Kim, E., Lee, S., Mian, M. F., Yun, S. U., Song, M., Yi, K. S.,
Ryu, S. H., and Suh, P. G. (2006) Crosstalk between Src and
major vault protein in epidermal growth factor-dependent cell
signalling. Febs J. 273, 793 – 804.</ref>, and is believed to be important in signaling regulation. In addition, MVP is subjected to dephosphorylation by SHP-2 <ref> Kolli, S., Zito, C. I., Mossink, M. H., Wiemer, E. A., and
Bennett, A. M. (2004) The major vault protein is a novel
substrate for the tyrosine phosphatase SHP-2 and scaffold
protein in epidermal growth factor signaling. J. Biol.
Chem. 279, 29374 – 29385. </ref> and poly-(ADP)-ribosylation by vPARP <ref> Kickhoefer, V. A., Siva, A. C., Kedersha, N. L., Inman, E. M.,
Ruland, C., Streuli, M., and Rome, L. H. (1999) The 193-kD
vault protein, VPARP, is a novel poly(ADP-ribose) polymerase.
J. Cell Biol. 146, 917 – 928. </ref> , but the impact of these molecular changes are not yet fully known.

==Vault particles and MVP dynamics and localizations==
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 <ref name=stein /> <ref> van Zon, A., Mossink, M. H., Scheper, R. J., Sonneveld, P.,
and Wiemer, E. A. (2003) The vault complex. Cell. Mol. Life
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.
(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 –
178.]]

</StructureSection>
== References ==

<references/>

File:Pdbnmr.jpg

2018-03-17T06:49:58Z

Idan Ben-Nachum: The structure of the two domain fragment of MVP, depicted by NMR. Taken from the 1Y7X entry in the PBD. credit to: Kozlov, G., Vavelyuk, O., Minailiuc, O., Banville, D., Gehring, K., and Ekiel, I. (2006) Solution structure of a two-repeat fragment of majo

The structure of the two domain fragment of MVP, depicted by NMR. Taken from the 1Y7X entry in the PBD. credit to: 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.

Major vault protein

2018-03-17T06:41:19Z

Idan Ben-Nachum:

==The Major Vault Protein==
<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 <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 ==
Though extremely ubiquitous, there is still controversy regarding MVP’s specific function, but all the same some hypotheses regarding MVP’s main role relies on their barrel-like shape due to the assumption that “form ever follows function”<ref> Suprenant, K. A. (2002) Vault ribonucleoprotein particles:
sarcophagi, gondolas, or safety deposit boxes? Biochemistry
41, 14447 – 14454</ref>. In addition, there are growing evidence regarding several aspects MVP might be relevant in:
===MVP and drug resistance===
MVP is thought to be identical to the human lung resistance protein (LRP) that is overexpressed in multiple chemotherapy resistance models <ref> Izquierdo, M. A., Scheffer, G. L., Flens, M. J., Shoemaker, R.
H., Rome, L. H., and Scheper, R. J. (1996) Relationship of
LRP-human major vault protein to in vitro and clinical
resistance to anticancer drugs. Cytotechnology 19, 191 – 197.</ref>. Though MVP is also overexpressed in drug resistant human cancer cells, its role in drug resistance has some contradictory observations: While on the one hand knockdown of MVP by siRNA has led to accumulation of drugs like doxorubicin, MVP(-/-) mice did not exhibited any hypersensitivity to drugs <ref> Mossink, M. H., van Zon, A., Franzel-Luiten, E., Schoester,M., Kickhoefer, V. A., Scheffer, G. L., Scheper, R. J.,Sonneveld, P., and Wiemer, E. A. (2002) Disruption of themurine major vault protein (MVP/LRP) gene does not induce hypersensitivity to cytostatics. Cancer Res. 62, 7298 – 7304. </ref>.
===MVP and apoptosis===
MVP was found to enhance the expression of the anti-apoptotic protein [[bcl-2]] in senescent human fibroblasts <ref> Ryu, S. J., An, H. J., Oh, Y. S., Choi, H. R., Ha, M. K., and Park, S. C. (2008) On the role of major vault protein in the resistance of senescent human diploid fibroblasts to apoptosis. Cell Death Differ. doi: 10.1038/cdd.2008.96.</ref>. By binding to [[COP1]], which is an [[E3 ligase]], MVP forms an interaction which is essential for the degradation of [[c-June]]. This degradation is important in senescent human fibroblasts regarding the modulation of the anti-apoptotic protein bcl-2, and it is reduced when MVP is subjected to UV light which causes it to be tyrosine-phosphorylated.
===MVP and vaults in signal regulation and transport platforms===
Though the inner cavity of the vault particle created by MVP was reported to accommodate an unknown inner mass <ref name=kong> Kong, L. B., Siva, A. C., Rome, L. H., and Stewart, P. L. (1999)
Structure of the vault, a ubiquitous celular component.
Structure Fold Des. 7, 371 – 379.</ref>, and though vaults have known qualities like rapid movement to [[lipid raft]]s, unique subcellular localization <ref> Slesina, M., Inman, E. M., Rome, L. H., and Volknandt, W.
(2005) Nuclear localization of the major vault protein in U373
cells. Cell Tissue Res. 321, 97 – 104.</ref> <ref> Herrmann, C., Golkaramnay, E., Inman, E., Rome, L., and
Volknandt, W. (1999) Recombinant major vault protein is
targeted to neuritic tips of PC12 cells. J. Cell Biol. 144, 1163 –
1172.</ref> <ref> Herrmann, C., Volknandt, W., Wittich, B., Kellner, R., and
Zimmermann, H. (1996) The major vault protein (MVP100) is
contained in cholinergic nerve terminals of electric ray
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.,
Gygi, S. P., Wiemer, E. A., and Pier, G. B. (2007) Host
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 name=stein> Steiner, E., Holzmann, K., Elbling, L., Micksche, M., and
Berger, W. (2006) Cellular functions of vaults and their
involvement in multidrug resistance. Curr. Drug Targets 7,
923 – 934. </ref> (that led some to hypothesize that MVP is a promiscuous transport vehicle), no consensus has been reached regarding MVP’s role in intracellular transport. Still, there are some known relations between MVP and signal transduction proteins:
* MVP binds to and is thought to help translocate [[PTEN]] through the [[NPC]]. PTEN is important in inhibiting the [[PI3K]]/[[AKT]] pathway which inhibits [[MAPK]] in the nucleus. This way, MVP is thought to reduce expression of [[cyclin D]] and in turn cause G0/G1 arrest<ref> Chung, J. H., and Eng, C. (2005) Nuclear-cytoplasmic
partitioning of phosphatase and tensin homologue deleted
on chromosome 10 (PTEN) differentially regulates the cell
cycle and apoptosis. Cancer Res. 65, 8096 – 8100</ref>.
* MVP is phosphorylated due to [[EGFR]] stimulation on tyrosine residues<ref> Yi, C., Li, S., Chen, X., Wiemer, E. A., Wang, J., Wei, N., and
Deng, X. W. (2005) Major vault protein, in concert with
constitutively photomorphogenic 1, negatively regulates cJun-mediated
activator protein 1 transcription in mammalian
cells. Cancer Res. 65, 5835 – 5840.</ref>, thus allowing it to bind to the MAPK [[Erk]] and the tyrosine phosphorylase [[SHP-2]]<ref name=kolli> Kolli, S., Zito, C. I., Mossink, M. H., Wiemer, E. A., and
Bennett, A. M. (2004) The major vault protein is a novel
substrate for the tyrosine phosphatase SHP-2 and scaffold
protein in epidermal growth factor signaling. J. Biol.
Chem. 279, 29374 – 29385. </ref>. Since the interaction between SHP-2 and MVP is achieved through [[SH2 domain]], it is not surprising that the [[Src]] protein was found to bind MVP as well <ref> Kim, E., Lee, S., Mian, M. F., Yun, S. U., Song, M., Yi, K. S.,
Ryu, S. H., and Suh, P. G. (2006) Crosstalk between Src and
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 />
* 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
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 ==
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.</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.

==The MVP gene, transcription, translation and post translation modifications==
The human MVP gene resides on chromosome 16p11.2. Upregulation of MVP can be caused by chemotherapy resistance <ref name=mossink /> <ref> Kickhoefer, V. A., Rajavel, K. S., Scheffer, G. L., Dalton, W.
S., Scheper, R. J., and Rome, L. H. (1998) Vaults are upregulated
in multidrug-resistant cancer cell lines. J. Biol.
Chem. 273, 8971 – 8974. </ref> <ref> Izquierdo, M. A., Scheffer, G. L., Flens, M. J., Shoemaker, R.
H., Rome, L. H., and Scheper, R. J. (1996) Relationship of
LRP-human major vault protein to in vitro and clinical
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
of the human major vault protein in astrocytic
brain tumor cells. Int. J. Cancer 94, 377 – 382. </ref>, senescence/aging <ref> Ryu, S. J., An, H. J., Oh, Y. S., Choi, H. R., Ha, M. K., and
Park, S. C. (2008) On the role of major vault protein in the
resistance of senescent human diploid fibroblasts to apoptosis.
Cell Death Differ. doi: 10.1038/cdd.2008.96. </ref> hyperthermia <ref> Stein, U., Jurchott, K., Schlafke, M., and Hohenberger, P.
(2002) Expression of multidrug resistance genes MVP,
MDR1, and MRP1 determined sequentially before, during,
and after hyperthermic isolated limb perfusion of soft tissue
sarcoma and melanoma patients. J. Clin. Oncol. 20, 3282 –
3292. </ref> and estradiol treatment <ref> Abbondanza, C., Rossi, V., Roscigno, A., Gallo, L., Belsito,
A., Piluso, G., Medici, N., Nigro, V., Molinari, A. M.,
Moncharmont, B., and Puca, G. A. (1998) Interaction of
vault particles with estrogen receptor in the MCF-7 breast
cancer cell. J. Cell Biol. 141, 1301 – 1310. </ref>. Other factors that elevate MVP expression are [[cytokine]]s like [[interferons γ]] <ref> Miracco, C., Maellaro, E., Pacenti, L., Del Bello, B.,
Valentini, M. A., Rubegni, P., Pirtoli, L., Volpi, C., Santopietro,
R., and Tosi, P. (2003) Evaluation of MDR1, LRP, MRP,
and topoisomerase IIalpha gene mRNA transcripts before
and after interferon-alpha, and correlation with the mRNA
expression level of the telomerase subunits hTERT and TEP1
in five unselected human melanoma cell lines. Int. J.
Oncol. 23, 213 – 220. </ref> <ref> Steiner, E., Holzmann, K., Pirker, C., Elbling, L., Micksche,
M., Sutterluty, H., and Berger, W. (2006) The major vault
protein is responsive to and interferes with interferongamma-mediated
STAT1 signals. J. Cell Sci. 119, 459 – 469. </ref>, while other like [[TNFα]] suppress it.
The murine and human MVP gene is TATA-less and lacks other core promotor elements. Several of MVP’s transcription factors are involved in cell development and differentiation, but also malignant transformation <ref> Fujii, T., Kawahara, A., Basaki, Y., Hattori, S., Nakashima,
K., Nakano, K., Shirouzu, K., Kohno, K., Yanagawa, T.,
Yamana, H., Nishio, K., Ono, M., Kuwano, M., and Kage, M.
(2008) Expression of HER2 and estrogen receptor alpha
depends upon nuclear localization of Y-box binding protein-1
in human breast cancers. Cancer Res. 68, 1504 – 1512. </ref>.
MVP is postulated to have posttranscriptional regulations, like stabilization of its mRNA <ref> Laurencot, C. M., Scheffer, G. L., Scheper, R. J., and
Shoemaker, R. H. (1997) Increased LRP mRNA expression
is associated with the MDR phenotype in intrinsically
resistant human cancer cell lines. Int. J. Cancer 72, 1021 – 1026. </ref> and alternative splicing in its 5’ UTR which represses its translation <ref> Holzmann, K., Ambrosch, I., Elbling, L., Micksche, M., and
Berger, W. (2001) A small upstream open reading frame
causes inhibition of human major vault protein expression
from a ubiquitous mRNA splice variant. FEBS Lett. 494, 99 –
104. </ref>. MVP degradation is thought to be control by the [[proteasome]] <ref> Sutovsky, P., Manandhar, G., Laurincik, J., Letko, J., Caamano,
J. N., Day, B. N., Lai, L., Prather, R. S., Sharpe-Timms, K.
L., Zimmer, R., and Sutovsky, M. (2005) Expression and
proteasomal degradation of the major vault protein (MVP) in
mammalian oocytes and zygotes. Reproduction 129, 269 – 282. </ref> <ref> Suprenant, K. A., Bloom, N., Fang, J., and Lushington, G.
(2007) The major vault protein is related to the toxic anion
resistance protein (TelA) family. J. Exp. Biol. 210, 946 – 955. </ref> <ref> Yi, C., Li, S., Chen, X., Wiemer, E. A., Wang, J., Wei, N., and
Deng, X. W. (2005) Major vault protein, in concert with
constitutively photomorphogenic 1, negatively regulates cJun-mediated
activator protein 1 transcription in mammalian
cells. Cancer Res. 65, 5835 – 5840 </ref>, but as of today no [[ubiquitin]]ation of vault or MVP has been confirmed.
MVP is subjected to phosphorylation by several proteins such as [[protein kinase C]], [[casein kinase II]] and [[Src kinase]] <ref> Ehrnsperger, C., and Volknandt, W. (2001) Major vault
protein is a substrate of endogenous protein kinases in CHO
and PC12 cells. Biol. Chem. 382, 1463 – 1471. </ref> <ref> Herrmann, C., Kellner, R., and Volknandt, W. (1998) Major
vault protein of electric ray is a phosphoprotein. Neurochem.
Res. 23, 39 – 46. </ref> <ref> Kim, E., Lee, S., Mian, M. F., Yun, S. U., Song, M., Yi, K. S.,
Ryu, S. H., and Suh, P. G. (2006) Crosstalk between Src and
major vault protein in epidermal growth factor-dependent cell
signalling. Febs J. 273, 793 – 804.</ref>, and is believed to be important in signaling regulation. In addition, MVP is subjected to dephosphorylation by SHP-2 <ref> Kolli, S., Zito, C. I., Mossink, M. H., Wiemer, E. A., and
Bennett, A. M. (2004) The major vault protein is a novel
substrate for the tyrosine phosphatase SHP-2 and scaffold
protein in epidermal growth factor signaling. J. Biol.
Chem. 279, 29374 – 29385. </ref> and poly-(ADP)-ribosylation by vPARP <ref> Kickhoefer, V. A., Siva, A. C., Kedersha, N. L., Inman, E. M.,
Ruland, C., Streuli, M., and Rome, L. H. (1999) The 193-kD
vault protein, VPARP, is a novel poly(ADP-ribose) polymerase.
J. Cell Biol. 146, 917 – 928. </ref> , but the impact of these molecular changes are not yet fully known.

==Vault particles and MVP dynamics and localizations==
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 <ref name=stein /> <ref> van Zon, A., Mossink, M. H., Scheper, R. J., Sonneveld, P.,
and Wiemer, E. A. (2003) The vault complex. Cell. Mol. Life
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.
(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 –
178.]]

</StructureSection>
== References ==

<references/>

Major vault protein

2018-03-16T18:41:26Z

Idan Ben-Nachum:

==The Major Vault Protein==
<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.

== Function and relevance ==
Though extremely ubiquitous, there is still controversy regarding MVP’s specific function, but all the same some hypotheses regarding MVP’s main role relies on their barrel-like shape due to the assumption that “form ever follows function”<ref> Suprenant, K. A. (2002) Vault ribonucleoprotein particles:
sarcophagi, gondolas, or safety deposit boxes? Biochemistry
41, 14447 – 14454</ref>. In addition, there are growing evidence regarding several aspects MVP might be relevant in:
===MVP and drug resistance===
MVP is thought to be identical to the human lung resistance protein (LRP) that is overexpressed in multiple chemotherapy resistance models <ref> Izquierdo, M. A., Scheffer, G. L., Flens, M. J., Shoemaker, R.
H., Rome, L. H., and Scheper, R. J. (1996) Relationship of
LRP-human major vault protein to in vitro and clinical
resistance to anticancer drugs. Cytotechnology 19, 191 – 197.</ref>. Though MVP is also overexpressed in drug resistant human cancer cells, its role in drug resistance has some contradictory observations: While on the one hand knockdown of MVP by siRNA has led to accumulation of drugs like doxorubicin, MVP(-/-) mice did not exhibited any hypersensitivity to drugs <ref> Mossink, M. H., van Zon, A., Franzel-Luiten, E., Schoester,M., Kickhoefer, V. A., Scheffer, G. L., Scheper, R. J.,Sonneveld, P., and Wiemer, E. A. (2002) Disruption of themurine major vault protein (MVP/LRP) gene does not induce hypersensitivity to cytostatics. Cancer Res. 62, 7298 – 7304. </ref>.
===MVP and apoptosis===
MVP was found to enhance the expression of the anti-apoptotic protein [[bcl-2]] in senescent human fibroblasts <ref> Ryu, S. J., An, H. J., Oh, Y. S., Choi, H. R., Ha, M. K., and Park, S. C. (2008) On the role of major vault protein in the resistance of senescent human diploid fibroblasts to apoptosis. Cell Death Differ. doi: 10.1038/cdd.2008.96.</ref>. By binding to [[COP1]], which is an [[E3 ligase]], MVP forms an interaction which is essential for the degradation of [[c-June]]. This degradation is important in senescent human fibroblasts regarding the modulation of the anti-apoptotic protein bcl-2, and it is reduced when MVP is subjected to UV light which causes it to be tyrosine-phosphorylated.
===MVP and vaults in signal regulation and transport platforms===
Though the inner cavity of the vault particle created by MVP was reported to accommodate an unknown inner mass <ref name=kong> Kong, L. B., Siva, A. C., Rome, L. H., and Stewart, P. L. (1999)
Structure of the vault, a ubiquitous celular component.
Structure Fold Des. 7, 371 – 379.</ref>, and though vaults have known qualities like rapid movement to [[lipid raft]]s, unique subcellular localization <ref> Slesina, M., Inman, E. M., Rome, L. H., and Volknandt, W.
(2005) Nuclear localization of the major vault protein in U373
cells. Cell Tissue Res. 321, 97 – 104.</ref> <ref> Herrmann, C., Golkaramnay, E., Inman, E., Rome, L., and
Volknandt, W. (1999) Recombinant major vault protein is
targeted to neuritic tips of PC12 cells. J. Cell Biol. 144, 1163 –
1172.</ref> <ref> Herrmann, C., Volknandt, W., Wittich, B., Kellner, R., and
Zimmermann, H. (1996) The major vault protein (MVP100) is
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.,
Golan, D. E., Zaidi, T., Coutinho-Sledge, Y. S., Gygi, M. P.,
Gygi, S. P., Wiemer, E. A., and Pier, G. B. (2007) Host
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
Berger, W. (2006) Cellular functions of vaults and their
involvement in multidrug resistance. Curr. Drug Targets 7,
923 – 934. </ref> (that led some to hypothesize that MVP is a promiscuous transport vehicle), no consensus has been reached regarding MVP’s role in intracellular transport. Still, there are some known relations between MVP and signal transduction proteins:
* MVP binds to and is thought to help translocate [[PTEN]] through the [[NPC]]. PTEN is important in inhibiting the [[PI3K]]/[[AKT]] pathway which inhibits [[MAPK]] in the nucleus. This way, MVP is thought to reduce expression of [[cyclin D]] and in turn cause G0/G1 arrest<ref> Chung, J. H., and Eng, C. (2005) Nuclear-cytoplasmic
partitioning of phosphatase and tensin homologue deleted
on chromosome 10 (PTEN) differentially regulates the cell
cycle and apoptosis. Cancer Res. 65, 8096 – 8100</ref>.
* MVP is phosphorylated due to [[EGFR]] stimulation on tyrosine residues<ref> Yi, C., Li, S., Chen, X., Wiemer, E. A., Wang, J., Wei, N., and
Deng, X. W. (2005) Major vault protein, in concert with
constitutively photomorphogenic 1, negatively regulates cJun-mediated
activator protein 1 transcription in mammalian
cells. Cancer Res. 65, 5835 – 5840.</ref>, thus allowing it to bind to the MAPK [[Erk]] and the tyrosine phosphorylase [[SHP-2]]<ref name=kolli> Kolli, S., Zito, C. I., Mossink, M. H., Wiemer, E. A., and
Bennett, A. M. (2004) The major vault protein is a novel
substrate for the tyrosine phosphatase SHP-2 and scaffold
protein in epidermal growth factor signaling. J. Biol.
Chem. 279, 29374 – 29385. </ref>. Since the interaction between SHP-2 and MVP is achieved through [[SH2 domain]], it is not surprising that the [[Src]] protein was found to bind MVP as well <ref> Kim, E., Lee, S., Mian, M. F., Yun, S. U., Song, M., Yi, K. S.,
Ryu, S. H., and Suh, P. G. (2006) Crosstalk between Src and
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 />
* 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 [149].
* 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[115].

== 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
are the answer, what is the question? Trends Cell Biol. 6, 174 – 178.</ref> <ref> Anderson, D. H., Kickhoefer, V. A., Sievers, S. A., Rome, L. H., and Eisenberg, D. (2007) Draft crystal structure of the vault shell at 9-A resolution. PLoS Biol. 5, e318. </ref> <ref> Kedersha, N. L., and Rome, L. H. (1990) Vaults: large
cytoplasmic RNP�s that associate with cytoskeletal elements. Mol. Biol. Rep. 14, 121 – 122. </ref>- around 90% within mammals <ref> 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> 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 human MVP gene resides on chromosome 16p11.2. Upregulation of MVP can be caused by chemotherapy resistance <ref name=mossink /> <ref> Kickhoefer, V. A., Rajavel, K. S., Scheffer, G. L., Dalton, W.
S., Scheper, R. J., and Rome, L. H. (1998) Vaults are upregulated
in multidrug-resistant cancer cell lines. J. Biol.
Chem. 273, 8971 – 8974. </ref> <ref> Izquierdo, M. A., Scheffer, G. L., Flens, M. J., Shoemaker, R.
H., Rome, L. H., and Scheper, R. J. (1996) Relationship of
LRP-human major vault protein to in vitro and clinical
resistance to anticancer drugs. Cytotechnology 19, 191 – 197. </ref> <ref> Steiner, E., Holzmann, K., Elbling, L., Micksche, M., and
Berger, W. (2006) Cellular functions of vaults and their
involvement in multidrug resistance. Curr. Drug Targets 7,
923 – 934.</ref> , malignant transformation <ref> Berger, W., Spiegl-Kreinecker, S., Buchroithner, J., Elbling,
L., Pirker, C., Fischer, J., and Micksche, M. (2001) Overexpression
of the human major vault protein in astrocytic
brain tumor cells. Int. J. Cancer 94, 377 – 382. </ref>, senescence/aging <ref> Ryu, S. J., An, H. J., Oh, Y. S., Choi, H. R., Ha, M. K., and
Park, S. C. (2008) On the role of major vault protein in the
resistance of senescent human diploid fibroblasts to apoptosis.
Cell Death Differ. doi: 10.1038/cdd.2008.96. </ref> hyperthermia <ref> Stein, U., Jurchott, K., Schlafke, M., and Hohenberger, P.
(2002) Expression of multidrug resistance genes MVP,
MDR1, and MRP1 determined sequentially before, during,
and after hyperthermic isolated limb perfusion of soft tissue
sarcoma and melanoma patients. J. Clin. Oncol. 20, 3282 –
3292. </ref> and estradiol treatment <ref> Abbondanza, C., Rossi, V., Roscigno, A., Gallo, L., Belsito,
A., Piluso, G., Medici, N., Nigro, V., Molinari, A. M.,
Moncharmont, B., and Puca, G. A. (1998) Interaction of
vault particles with estrogen receptor in the MCF-7 breast
cancer cell. J. Cell Biol. 141, 1301 – 1310. </ref>. Other factors that elevate MVP expression are [[cytokine]]s like [[interferons γ]] <ref> Miracco, C., Maellaro, E., Pacenti, L., Del Bello, B.,
Valentini, M. A., Rubegni, P., Pirtoli, L., Volpi, C., Santopietro,
R., and Tosi, P. (2003) Evaluation of MDR1, LRP, MRP,
and topoisomerase IIalpha gene mRNA transcripts before
and after interferon-alpha, and correlation with the mRNA
expression level of the telomerase subunits hTERT and TEP1
in five unselected human melanoma cell lines. Int. J.
Oncol. 23, 213 – 220. </ref> <ref> Steiner, E., Holzmann, K., Pirker, C., Elbling, L., Micksche,
M., Sutterluty, H., and Berger, W. (2006) The major vault
protein is responsive to and interferes with interferongamma-mediated
STAT1 signals. J. Cell Sci. 119, 459 – 469. </ref>, while other like [[TNFα]] suppress it.
The murine and human MVP gene is TATA-less and lacks other core promotor elements. Several of MVP’s transcription factors are involved in cell development and differentiation, but also malignant transformation <ref> Fujii, T., Kawahara, A., Basaki, Y., Hattori, S., Nakashima,
K., Nakano, K., Shirouzu, K., Kohno, K., Yanagawa, T.,
Yamana, H., Nishio, K., Ono, M., Kuwano, M., and Kage, M.
(2008) Expression of HER2 and estrogen receptor alpha
depends upon nuclear localization of Y-box binding protein-1
in human breast cancers. Cancer Res. 68, 1504 – 1512. </ref>.
MVP is postulated to have posttranscriptional regulations, like stabilization of its mRNA <ref> Laurencot, C. M., Scheffer, G. L., Scheper, R. J., and
Shoemaker, R. H. (1997) Increased LRP mRNA expression
is associated with the MDR phenotype in intrinsically
resistant human cancer cell lines. Int. J. Cancer 72, 1021 – 1026. </ref> and alternative splicing in its 5’ UTR which represses its translation <ref> Holzmann, K., Ambrosch, I., Elbling, L., Micksche, M., and
Berger, W. (2001) A small upstream open reading frame
causes inhibition of human major vault protein expression
from a ubiquitous mRNA splice variant. FEBS Lett. 494, 99 –
104. </ref>. MVP degradation is thought to be control by the [[proteasome]] <ref> Sutovsky, P., Manandhar, G., Laurincik, J., Letko, J., Caamano,
J. N., Day, B. N., Lai, L., Prather, R. S., Sharpe-Timms, K.
L., Zimmer, R., and Sutovsky, M. (2005) Expression and
proteasomal degradation of the major vault protein (MVP) in
mammalian oocytes and zygotes. Reproduction 129, 269 – 282. </ref> <ref> Suprenant, K. A., Bloom, N., Fang, J., and Lushington, G.
(2007) The major vault protein is related to the toxic anion
resistance protein (TelA) family. J. Exp. Biol. 210, 946 – 955. </ref> <ref> Yi, C., Li, S., Chen, X., Wiemer, E. A., Wang, J., Wei, N., and
Deng, X. W. (2005) Major vault protein, in concert with
constitutively photomorphogenic 1, negatively regulates cJun-mediated
activator protein 1 transcription in mammalian
cells. Cancer Res. 65, 5835 – 5840 </ref>, but as of today no [[ubiquitin]]ation of vault or MVP has been confirmed.
MVP is subjected to phosphorylation by several proteins such as [[protein kinase C]], [[casein kinase II]] and [[Src kinase]] <ref> Ehrnsperger, C., and Volknandt, W. (2001) Major vault
protein is a substrate of endogenous protein kinases in CHO
and PC12 cells. Biol. Chem. 382, 1463 – 1471. </ref> <ref> Herrmann, C., Kellner, R., and Volknandt, W. (1998) Major
vault protein of electric ray is a phosphoprotein. Neurochem.
Res. 23, 39 – 46. </ref> <ref> Kim, E., Lee, S., Mian, M. F., Yun, S. U., Song, M., Yi, K. S.,
Ryu, S. H., and Suh, P. G. (2006) Crosstalk between Src and
major vault protein in epidermal growth factor-dependent cell
signalling. Febs J. 273, 793 – 804.</ref>, and is believed to be important in signaling regulation. In addition, MVP is subjected to dephosphorylation by SHP-2 <ref> Kolli, S., Zito, C. I., Mossink, M. H., Wiemer, E. A., and
Bennett, A. M. (2004) The major vault protein is a novel
substrate for the tyrosine phosphatase SHP-2 and scaffold
protein in epidermal growth factor signaling. J. Biol.
Chem. 279, 29374 – 29385. </ref> and poly-(ADP)-ribosylation by vPARP <ref> Kickhoefer, V. A., Siva, A. C., Kedersha, N. L., Inman, E. M.,
Ruland, C., Streuli, M., and Rome, L. H. (1999) The 193-kD
vault protein, VPARP, is a novel poly(ADP-ribose) polymerase.
J. Cell Biol. 146, 917 – 928. </ref> , but the impact of these molecular changes are not yet fully known.

==Vault particles and MVP dynamics and localizations==
Vaults have been shown to occasionally open up into a flower-like structure with 8 petals (figure 1) [7, 20], 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 [20,21,34]. 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[].
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 [14,35,99,113-115].
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 [100].
[[Image:Flower.jpg| thumb | Figure 1- 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 –
178.]]

</StructureSection>
== References ==

<references/>

Major vault protein

2018-03-16T18:05:38Z

Idan Ben-Nachum:

Major vault protein

2018-03-16T17:12:46Z

Idan Ben-Nachum:

Major vault protein

2018-03-16T17:07:07Z

Idan Ben-Nachum:

Major vault protein

2018-03-16T16:50:40Z

Idan Ben-Nachum:

Major vault protein

2018-03-16T16:45:55Z

Idan Ben-Nachum:

File:Flower.jpg

2018-03-16T16:38:21Z

Idan Ben-Nachum: the open flower shape that MVP can assume. 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 – 178.

the open flower shape that MVP can assume. 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 – 178.

Major vault protein

2018-03-16T16:23:27Z

Idan Ben-Nachum:

Major vault protein

2018-03-16T15:56:04Z

Idan Ben-Nachum:

Major vault protein

2018-03-16T15:53:58Z

Idan Ben-Nachum:

Major vault protein

2018-03-16T15:10:09Z

Idan Ben-Nachum:

Major vault protein

2018-03-16T14:56:31Z

Idan Ben-Nachum:

Major vault protein

2018-03-16T14:05:15Z

Idan Ben-Nachum: First time creating the MVP page, by Idan Ben Nachum

Elizeu/sandbox/citocromo c

2018-03-14T19:19:32Z

Idan Ben-Nachum:

==this is better==
<Structure load='1qu7' size='350' frame='true' align='right' color='black' caption='Citocromo_c (PDB entry [[1ycc]])' scene='55/559112/Citc_spacefill_cpk/1' />

<scene name='55/559112/Citc_spacefill_cpk/1'>Esta é a proteína citocromo c.</scene> Sendo um dos componentes da cadeia respiratória, o citocromo c desempenha função transportadora de elétrons (participa de reação de oxirredução).

1 - <scene name='55/559112/Citc_spacefill_cpk/3'>Como essa proteína se classifica quanto à sua forma?</scene>

2 - <scene name='55/559112/Citc_spacefill_cpk/7'>Quantas cadeias polipeptídicas constituem o citocromo c?</scene>

3 - <scene name='55/559112/Citc_spacefill_cpk/4'>Identifique, pelas cores, os diferentes tipos de arranjos próprios da sua estrutura secundária.</scene>

4 - <scene name='55/559112/Citc_spacefill_cpk/8'>Quantos grupos prostéticos estão presentes no citocromo c?</scene>

5 - <scene name='55/559112/Citc_spacefill_cpk/9'>Aponte (com o mouse) para os diferentes átomos do grupo prostético e deduza qual dos elementos é responsável pela transferência de elétrons no citocromo c.</scene>

== ==
- Voltar para a página principal (PROTEINS: RELATIONSHIP BETWEEN STRUCTURE AND FUNCTION) [http://proteopedia.org/wiki/index.php/Elizeu/sandbox]

- Seguir para a próxima proteína (colágeno) [http://proteopedia.org/wiki/index.php/Col%C3%A1geno]