Major vault protein

From Proteopedia

The Major Vault Protein

spinqualitylabelsall models The outer shell of the rat Vault particle (PDB code 2qzv) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image 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 vPARP (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 macrophages. 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 [1]. Contents 1 Function and relevance 1.1 MVP and drug resistance 1.2 MVP and apoptosis 1.3 MVP and vaults in signal regulation and transport platforms 2 Structural highlights 3 The MVP gene, transcription, translation and post translation modifications 4 Vault particles and MVP dynamics and localizations 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”[2]. 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 [3]. 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 [4]. MVP and apoptosis MVP was found to enhance the expression of the anti-apoptotic protein bcl-2 in senescent human fibroblasts [5]. 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 [6], and though vaults have known qualities like rapid movement to lipid rafts, unique subcellular localization [7] [8] [9] [10] and in vitro and clinical correlation with drug resistance [11] (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[12]. MVP is phosphorylated due to EGFR stimulation on tyrosine residues[13], thus allowing it to bind to the MAPK Erk and the tyrosine phosphorylase SHP-2[14]. 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 [15]. This data is thought to indicate that MVP might have a scaffolding function for signal transduction.[14] 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 [16]. 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[10]. 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 forms the waist of the particle while their 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 [17]. 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 [6] [17] [18] - around 90% within mammals [19] [20] There are several domains within MVP, among the most important is the highly conserved 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 hands in [21] , 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 (Figure 1) of multiple MVP domains [22] , in a way similar to that found in integrins. 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 [20] [23] [24] [11] , malignant transformation [25], senescence/aging [26] hyperthermia [27] and estradiol treatment [28]. Other factors that elevate MVP expression are cytokines like interferons γ [29] [30], 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 [31]. MVP is postulated to have posttranscriptional regulations, like stabilization of its mRNA [32] and alternative splicing in its 5’ UTR which represses its translation [33]. MVP degradation is thought to be control by the proteasome [34] [35] [36], but as of today no ubiquitination 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 [37] [38] [39], and is believed to be important in signaling regulation. In addition, MVP is subjected to dephosphorylation by SHP-2 [40] and poly-(ADP)-ribosylation by vPARP [41] , 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) [18], 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 [11] [42]. 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 [43]. 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 [19] [25] [43] [10]. 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 microtubules [44]. 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.

3D structures of major vault protein

Updated on 23-January-2019

4v60, 6bp7, 6bp8, 4hl8, 2qzv – MVP – rat
1y7x – MVP R3-R4 residues 113-221– human - NMR
3gf5, 3gnf, 3gng – MVP residues R1-R7 1-383 – mouse

References

1. ↑ 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.‏
2. ↑ Suprenant, K. A. (2002) Vault ribonucleoprotein particles: sarcophagi, gondolas, or safety deposit boxes? Biochemistry 41, 14447 – 14454
3. ↑ 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.
4. ↑ 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.
5. ↑ 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.
6. ↑ ^{6.0 6.1} Kong, L. B., Siva, A. C., Rome, L. H., and Stewart, P. L. (1999) Structure of the vault, a ubiquitous cellular component. Structure Fold Des. 7, 371 – 379.
7. ↑ 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.
8. ↑ 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.
9. ↑ 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.
10. ↑ ^{10.0 10.1 10.2} 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.
11. ↑ ^{11.0 11.1 11.2} 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.
12. ↑ 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
13. ↑ 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.
14. ↑ ^{14.0 14.1} 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.
15. ↑ 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.
16. ↑ 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.
17. ↑ ^{17.0 17.1} 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.
18. ↑ ^{18.0 18.1} 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.
19. ↑ ^{19.0 19.1} 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.
20. ↑ ^{20.0 20.1} 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.
21. ↑ 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.
22. ↑ 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
23. ↑ 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.
24. ↑ 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.
25. ↑ ^{25.0 25.1} 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.
26. ↑ 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.
27. ↑ 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.
28. ↑ 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.
29. ↑ 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.
30. ↑ 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.
31. ↑ 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.
32. ↑ 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.
33. ↑ 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.
34. ↑ 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.
35. ↑ 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.
36. ↑ 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
37. ↑ 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.
38. ↑ Herrmann, C., Kellner, R., and Volknandt, W. (1998) Major vault protein of electric ray is a phosphoprotein. Neurochem. Res. 23, 39 – 46.
39. ↑ 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.
40. ↑ 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.
41. ↑ 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.
42. ↑ 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.
43. ↑ ^{43.0 43.1} 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.
44. ↑ 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.