Vault (organelle)

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Vault, N-terminal repeat domain
Qiong Long Ti .jpg
Structure of the Vault complex from rat liver. [1]
Identifiers
SymbolVault
Pfam PF01505
InterPro IPR002499
PROSITE PDOC51224
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 2ZUO 2ZV4 2ZV5

The vault or vault cytoplasmic ribonucleoprotein is a eukaryotic organelle whose function is not yet fully understood. Discovered and isolated by Nancy Kedersha and Leonard Rome in 1986, [2] vaults are cytoplasmic organelles which, when negative-stained and viewed under an electron microscope, resemble the arches of a cathedral's vaulted ceiling, with 39-fold (or D39d) symmetry. [1] They are present in many types of eukaryotic cells, and appear to be highly conserved among eukaryotes. [3]

Contents

Morphology

Vaults are large ribonucleoprotein particles. About 3 times the size of a ribosome and weighing approximately 13 MDa, they are found in most eukaryotic cells and all higher eukaryotes. They measure 34 nm by 60 nm from a negative stain, 26 nm by 49 nm from cryo-electron microscopy, and 35 nm by 59 nm from STEM. [4] The vaults consist primarily of proteins, making it difficult to stain with conventional techniques.

Structure

The protein structure consists of an outer shell composed of 78 copies of the ~100 kDa major vault protein (MVP). Inside are two associated vault proteins, TEP1 and VPARP. TEP1, also known as the telomerase-associated protein 1, [5] is 290 kDa and VPARP (also known as PARP4) is related to poly (ADP-ribose) polymerase (PARP) and is 193 kDa. [6] Vaults from higher eukaryotes also contain one or several small vault RNAs (vRNAs, also known as vtRNAs) of 86–141 bases within. [7]

The MVP subunits are composed head-to-head, with the N-termini of each half-vault facing each other. From the N-terminal to the C-terminal, a MVP subunit folds into 9 repeat domains, 1 band7-like shoulder domain, 1 cap-helix domain, and 1 cap-ring domain, corresponding to the shape of the vault shell. VPARP binds to repeat domain #4. TEP1, itself a ring due to the WD40 repeat, binds to the cap domain, with one particular type of vRNA plugging the cap. [8]

Function

Despite not being fully elucidated, vaults have been associated with the nuclear pore complexes and their octagonal shape appears to support this. [9] [10] Vaults have been implicated in a broad range of cellular functions including nuclear-cytoplasmic transport, mRNA localization, drug resistance, cell signaling, nuclear pore assembly, and innate immunity. [11] The three vault proteins (MVP, VPARP, and TEP1) have each been knocked out individually and in combination (VPARP and TEP1) in mice. [12] [13] [14] All of the knockout mice are viable and no major phenotypic alterations have been observed. Dictyostelium encode three different MVPs, two of which have been knocked out singly and in combination. [15] The only phenotype seen in the Dictyostelium double knockout was growth retardation under nutritional stress. [16] If vaults are involved in essential cellular functions, it seems likely that redundant systems exist that can ameliorate their loss.

Association with cancer

In the late 1990s, researchers found that vaults (especially the MVP) were over-expressed in cancer patients who were diagnosed with multidrug resistance, that is the resistance against many chemotherapy treatments. [17] Although this does not prove that increased number of vaults led to drug resistance, it does hint at some sort of involvement. This has potential in discovering the mechanisms behind drug-resistance in tumor cells and improving anticancer drugs. [15]

Evolutionary conservation

Vaults have been identified in mammals, amphibians, avians and Dictyostelium discoideum . [3] The Vault model used by the Pfam database identifies homologues in Paramecium tetraurelia , Kinetoplastida, many vertebrates, a cnidarian (starlet sea anemone), molluscs, Trichoplax adhaerens , flatworms, Echinococcus granulosus and Choanoflagellate. [18]

Although vaults have been observed in many eukaryotic species, a few species do not appear to have the ribonucleoprotein. These include: [19]

These four species are model organisms for plants, nematodes, animal genetics and fungi respectively. Despite these exceptions, the high degree of similarity of vaults in organisms that do have them implies some sort of evolutionary importance. [3]

Homologs of the major vault protein has been computationally found in bacteria. Cyanobacterial sequences appear most similar. [20] [21] Pfam is also able to identify some such homologs. [18]

Vault engineering

The Rome lab at UCLA has collaborated with a number of groups to use the baculovirus system to produce large quantities of vaults. When the major vault protein (MVP) is expressed in insect cells, vault particles are assembled on polyribosomes in the cytoplasm. [22] By using molecular genetic techniques to modify the gene encoding the major vault protein, vault particles have been produced with chemically active peptides attached to their sequence. These modified proteins are incorporated into the inside of the vault particle without altering its basic structure. Proteins and peptides can also be packaged into vaults by attachment of a packaging domain derived from the VPARP protein. [16] A number of modified vault particles have been produced in order to test the concept that vaults can be bio-engineered to allow their use in a wide variety of biological applications including drug delivery, biological sensors, enzyme delivery, controlled release, and environmental remediation.

A vault has been packaged with a chemokine for potential use to activate the immune system to attack lung cancer, and this approach has undergone phase I trials. [23] [24]

See also

Related Research Articles

The signal recognition particle (SRP) is an abundant, cytosolic, universally conserved ribonucleoprotein that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes.

A signal peptide is a short peptide present at the N-terminus of most newly synthesized proteins that are destined toward the secretory pathway. These proteins include those that reside either inside certain organelles, secreted from the cell, or inserted into most cellular membranes. Although most type I membrane-bound proteins have signal peptides, the majority of type II and multi-spanning membrane-bound proteins are targeted to the secretory pathway by their first transmembrane domain, which biochemically resembles a signal sequence except that it is not cleaved. They are a kind of target peptide.

<span class="mw-page-title-main">Cajal body</span>

Cajal bodies (CBs) also coiled bodies, are spherical nuclear bodies of 0.3–1.0 µm in diameter found in the nucleus of proliferative cells like embryonic cells and tumor cells, or metabolically active cells like neurons. CBs are membrane-less organelles and largely consist of proteins and RNA. They were first reported by Santiago Ramón y Cajal in 1903, who called them nucleolar accessory bodies due to their association with the nucleoli in neuronal cells. They were rediscovered with the use of the electron microscope (EM) and named coiled bodies, according to their appearance as coiled threads on EM images, and later renamed after their discoverer. Research on CBs was accelerated after discovery and cloning of the marker protein p80/Coilin. CBs have been implicated in RNA-related metabolic processes such as the biogenesis, maturation and recycling of snRNPs, histone mRNA processing and telomere maintenance. CBs assemble RNA which is used by telomerase to add nucleotides to the ends of telomeres.

<span class="mw-page-title-main">Nucleoprotein</span> Type of protein

Nucleoproteins are proteins conjugated with nucleic acids. Typical nucleoproteins include ribosomes, nucleosomes and viral nucleocapsid proteins.

In cellular biology, P-bodies, or processing bodies, are distinct foci formed by phase separation within the cytoplasm of a eukaryotic cell consisting of many enzymes involved in mRNA turnover. P-bodies are highly conserved structures and have been observed in somatic cells originating from vertebrates and invertebrates, plants and yeast. To date, P-bodies have been demonstrated to play fundamental roles in general mRNA decay, nonsense-mediated mRNA decay, adenylate-uridylate-rich element mediated mRNA decay, and microRNA (miRNA) induced mRNA silencing. Not all mRNAs which enter P-bodies are degraded, as it has been demonstrated that some mRNAs can exit P-bodies and re-initiate translation. Purification and sequencing of the mRNA from purified processing bodies showed that these mRNAs are largely translationally repressed upstream of translation initiation and are protected from 5' mRNA decay.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are complexes of RNA and protein present in the cell nucleus during gene transcription and subsequent post-transcriptional modification of the newly synthesized RNA (pre-mRNA). The presence of the proteins bound to a pre-mRNA molecule serves as a signal that the pre-mRNA is not yet fully processed and therefore not ready for export to the cytoplasm. Since most mature RNA is exported from the nucleus relatively quickly, most RNA-binding protein in the nucleus exist as heterogeneous ribonucleoprotein particles. After splicing has occurred, the proteins remain bound to spliced introns and target them for degradation.

<span class="mw-page-title-main">LSm</span>

In molecular biology, LSm proteins are a family of RNA-binding proteins found in virtually every cellular organism. LSm is a contraction of 'like Sm', because the first identified members of the LSm protein family were the Sm proteins. LSm proteins are defined by a characteristic three-dimensional structure and their assembly into rings of six or seven individual LSm protein molecules, and play a large number of various roles in mRNA processing and regulation.

<span class="mw-page-title-main">Vault RNA</span>

Many eukaryotic cells contain large ribonucleoprotein particles in the cytoplasm known as vaults. The vault complex comprises the major vault protein (MVP), two minor vault proteins, and a variety of small untranslated RNA molecules known as vault RNAs only found in higher eukaryotes. These molecules are transcribed by RNA polymerase III.

snRNP70 Protein-coding gene in the species Homo sapiens

snRNP70 also known as U1 small nuclear ribonucleoprotein 70 kDa is a protein that in humans is encoded by the SNRNP70 gene. snRNP70 is a small nuclear ribonucleoprotein that associates with U1 spliceosomal RNA, forming the U1snRNP a core component of the spliceosome. The U1-70K protein and other components of the spliceosome complex form detergent-insoluble aggregates in both sporadic and familial human cases of Alzheimer's disease. U1-70K co-localizes with Tau in neurofibrillary tangles in Alzheimer's disease.

<span class="mw-page-title-main">Small nuclear ribonucleoprotein D1</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein Sm D1 is a protein that in humans is encoded by the SNRPD1 gene.

<span class="mw-page-title-main">Major vault protein</span> Protein-coding gene in the species Homo sapiens

Major vault protein is a protein that in humans is encoded by the MVP gene. 78 copies of the protein assemble into the large compartments called vaults.

<span class="mw-page-title-main">SNRPB</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein-associated proteins B and B' is a protein that in humans is encoded by the SNRPB gene.

<span class="mw-page-title-main">Small nuclear ribonucleoprotein D2</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein Sm D2 is a protein that in humans is encoded by the SNRPD2 gene. It belongs to the small nuclear ribonucleoprotein core protein family, and is required for pre-mRNA splicing and small nuclear ribonucleoprotein biogenesis. Alternative splicing occurs at this locus and two transcript variants encoding the same protein have been identified.

<span class="mw-page-title-main">Small nuclear ribonucleoprotein polypeptide E</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein E is a protein that in humans is encoded by the SNRPE gene.

<span class="mw-page-title-main">Small nuclear ribonucleoprotein polypeptide F</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein F is a protein that in humans is encoded by the SNRPF gene.

<span class="mw-page-title-main">PARP4</span> Enzyme

Poly [ADP-ribose] polymerase 4 is an enzyme that in humans is encoded by the PARP4 gene.

<span class="mw-page-title-main">SNRPB2</span> Protein-coding gene in the species Homo sapiens

U2 small nuclear ribonucleoprotein B is a protein that in humans is encoded by the SNRPB2 gene.

<span class="mw-page-title-main">TEP1</span> Protein-coding gene in the species Homo sapiens

Telomerase protein component 1 is an enzyme that in humans is encoded by the TEP1 gene.

Leonard H. Rome is a cell biologist and biochemist who has been a faculty member of the David Geffen School of Medicine at UCLA, since he joined the Department of Biological Chemistry there, in 1979. He became a full professor in 1988 and has also served as the Senior Associate Dean for Research in the Geffen School of Medicine from 1997 to 2012. He is the Associate Director of the California NanoSystems Institute (CNSI) since 2004, and was Interim Director from 2007-2009. In addition, he served from 2001 to 2005 as University of California, Los Angeles (UCLA) Associate Vice Chancellor for Research for the Life and Health Sciences.

Nancy Kedersha is an American cell biologist and micrographer. She got her Ph.D. from Rutgers University where she worked in Richard Berg's lab studying the characteristics and assembly of prolyl hydroxylases. Afterwards she joined Leonard Rome's lab at UCLA as a post-doctoral fellow where she co-discovered the vault (organelle). Subsequently, she worked at ImmunoGen Inc. where she worked on staining and photographing different cancer cells. Currently, she works as an instructor of medicine at Brigham and Women's Hospital in Paul Anderson's lab where her work focuses on studying stress granules formation. In addition to her contributions as a scientist, Kedersha has been quite successful in different microscopy competitions. She is a four-time Nikon Small World finalist and in 2011 she won the Lennart Nilsson Award.

References

  1. 1 2 Tanaka H, Kato K, Yamashita E, Sumizawa T, Zhou Y, Yao M, Iwasaki K, Yoshimura M, Tsukihara T (January 2009). "The structure of rat liver vault at 3.5 angstrom resolution". Science. 323 (5912): 384–8. Bibcode:2009Sci...323..384T. doi:10.1126/science.1164975. PMID   19150846. S2CID   2072790.
  2. ↑ Kedersha NL, Rome LH (September 1986). "Isolation and characterization of a novel ribonucleoprotein particle: large structures contain a single species of small RNA". The Journal of Cell Biology. 103 (3): 699–709. doi:10.1083/jcb.103.3.699. PMC   2114306 . PMID   2943744.
  3. 1 2 3 Kedersha NL, Miquel MC, Bittner D, Rome LH (April 1990). "Vaults. II. Ribonucleoprotein structures are highly conserved among higher and lower eukaryotes". The Journal of Cell Biology. 110 (4): 895–901. doi:10.1083/jcb.110.4.895. PMC   2116106 . PMID   1691193.
  4. ↑ Kedersha NL, Heuser JE, Chugani DC, Rome LH (January 1991). "Vaults. III. Vault ribonucleoprotein particles open into flower-like structures with octagonal symmetry". The Journal of Cell Biology. 112 (2): 225–35. doi:10.1083/jcb.112.2.225. PMC   2288824 . PMID   1988458.
  5. ↑ Kickhoefer VA, Stephen AG, Harrington L, Robinson MO, Rome LH (November 1999). "Vaults and telomerase share a common subunit, TEP1". The Journal of Biological Chemistry. 274 (46): 32712–7. doi: 10.1074/jbc.274.46.32712 . PMID   10551828.
  6. ↑ Kickhoefer VA, Siva AC, Kedersha NL, Inman EM, Ruland C, Streuli M, Rome LH (September 1999). "The 193-kD vault protein, VPARP, is a novel poly(ADP-ribose) polymerase". The Journal of Cell Biology. 146 (5): 917–28. doi:10.1083/jcb.146.5.917. PMC   2169495 . PMID   10477748.
  7. ↑ van Zon A, Mossink MH, Scheper RJ, Sonneveld P, Wiemer EA (September 2003). "The vault complex". Cellular and Molecular Life Sciences. 60 (9): 1828–37. doi:10.1007/s00018-003-3030-y. PMID   14523546. S2CID   21196262.
  8. ↑ Tanaka, Hideaki; Tsukihara, Tomitake (2012). "Structural studies of large nucleoprotein particles, vaults". Proceedings of the Japan Academy, Series B. 88 (8): 416–433. Bibcode:2012PJAB...88..416T. doi:10.2183/pjab.88.416. PMC   3491081 . PMID   23060231.
  9. ↑ Chugani DC, Rome LH, Kedersha NL (September 1993). "Evidence that vault ribonucleoprotein particles localize to the nuclear pore complex". Journal of Cell Science. 106 ( Pt 1): 23–9. doi:10.1242/jcs.106.1.23. PMID   8270627.
  10. ↑ Unwin PN, Milligan RA (April 1982). "A large particle associated with the perimeter of the nuclear pore complex". The Journal of Cell Biology. 93 (1): 63–75. doi:10.1083/jcb.93.1.63. PMC   2112107 . PMID   7068761.
  11. ↑ Berger W, Steiner E, Grusch M, Elbling L, Micksche M (January 2009). "Vaults and the major vault protein: novel roles in signal pathway regulation and immunity". Cellular and Molecular Life Sciences. 66 (1): 43–61. doi:10.1007/s00018-008-8364-z. PMID   18759128. S2CID   6326163.
  12. ↑ Kickhoefer VA, Liu Y, Kong LB, Snow BE, Stewart PL, Harrington L, Rome LH (January 2001). "The Telomerase/vault-associated protein TEP1 is required for vault RNA stability and its association with the vault particle". The Journal of Cell Biology. 152 (1): 157–64. doi:10.1083/jcb.152.1.157. PMC   2193651 . PMID   11149928.
  13. ↑ Liu Y, Snow BE, Hande MP, Baerlocher G, Kickhoefer VA, Yeung D, Wakeham A, Itie A, Siderovski DP, Lansdorp PM, Robinson MO, Harrington L (November 2000). "Telomerase-associated protein TEP1 is not essential for telomerase activity or telomere length maintenance in vivo". Molecular and Cellular Biology. 20 (21): 8178–84. doi:10.1128/mcb.20.21.8178-8184.2000. PMC   86427 . PMID   11027287.
  14. ↑ Mossink MH, van Zon A, Fränzel-Luiten E, Schoester M, Kickhoefer VA, Scheffer GL, Scheper RJ, Sonneveld P, Wiemer EA (December 2002). "Disruption of the murine major vault protein (MVP/LRP) gene does not induce hypersensitivity to cytostatics". Cancer Research. 62 (24): 7298–304. PMID   12499273.
  15. 1 2 Kickhoefer VA, Vasu SK, Rome LH (May 1996). "Vaults are the answer, what is the question?". Trends in Cell Biology. 6 (5): 174–8. doi:10.1016/0962-8924(96)10014-3. PMID   15157468.
  16. 1 2 Rome LH, Kickhoefer VA (February 2013). "Development of the vault particle as a platform technology". ACS Nano. 7 (2): 889–902. doi:10.1021/nn3052082. PMID   23267674.
  17. ↑ Mossink MH, van Zon A, Scheper RJ, Sonneveld P, Wiemer EA (October 2003). "Vaults: a ribonucleoprotein particle involved in drug resistance?". Oncogene. 22 (47): 7458–67. doi: 10.1038/sj.onc.1206947 . PMID   14576851.
  18. 1 2 http://pfam.xfam.org/family/PF01505 Major Vault Protein repeat Pfam family
  19. ↑ Rome L, Kedersha N, Chugani D (August 1991). "Unlocking vaults: organelles in search of a function". Trends in Cell Biology. 1 (2–3): 47–50. doi:10.1016/0962-8924(91)90088-Q. PMID   14731565.
  20. ↑ Daly, TK; Sutherland-Smith, AJ; Penny, D (2013). "In silico resurrection of the major vault protein suggests it is ancestral in modern eukaryotes". Genome Biology and Evolution. 5 (8): 1567–83. doi: 10.1093/gbe/evt113 . PMC   3762200 . PMID   23887922.
  21. ↑ Sokolskyi, Tymofii (December 12, 2019). "Bacterial Major Vault Protein homologs shed new light on origins of the enigmatic organelle". bioRxiv   10.1101/872010 .
  22. ↑ Mrazek J, Toso D, Ryazantsev S, Zhang X, Zhou ZH, Fernandez BC, Kickhoefer VA, Rome LH (November 2014). "Polyribosomes are molecular 3D nanoprinters that orchestrate the assembly of vault particles". ACS Nano. 8 (11): 11552–9. doi:10.1021/nn504778h. PMC   4245718 . PMID   25354757.
  23. ↑ Sharma S, Zhu L, Srivastava MK, Harris-White M, Huang M, Lee JM, Rosen F, Lee G, Wang G, Kickhoefer V, Rome LH, Baratelli F, St John M, Reckamp K, Chul-Yang S, Hillinger S, Strieter R, Dubinett S (January 2013). "CCL21 Chemokine Therapy for Lung Cancer". International Trends in Immunity. 1 (1): 10–15. PMC   4175527 . PMID   25264541.
  24. ↑ Kar UK, Srivastava MK, Andersson A, Baratelli F, Huang M, Kickhoefer VA, Dubinett SM, Rome LH, Sharma S (May 2011). "Novel CCL21-vault nanocapsule intratumoral delivery inhibits lung cancer growth". PLOS ONE. 6 (5): e18758. Bibcode:2011PLoSO...618758K. doi: 10.1371/journal.pone.0018758 . PMC   3086906 . PMID   21559281.
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