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187  structures 89  species 1  interaction 555  sequences 11  architectures

Family: Vault (PF01505)

Summary: Major Vault Protein repeat

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This is the Wikipedia entry entitled "Vault (organelle)". More...

Vault (organelle) Edit Wikipedia article

Vault Particle
穹窿体.jpg
Structure of the Vault complex from rat liver.[1]
Identifiers
Symbol Vault
Pfam PF01505
InterPro IPR002499
PROSITE PDOC51224

The vault or vault cytoplasmic ribonucleoprotein is a eukaryotic organelle whose function is not fully understood. Discovered and isolated by cell biologist Nancy Kedersha and biochemist 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 vaulted ceiling, with 39-fold symmetry.[1] They are present in many types of eukaryotic cells and appear to be highly conserved amongst eukaryotes.[3]

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. 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]

Function

Despite not being fully elucidated, vaults have been associated with the nuclear pore complexes and their octagonal shape appears to support this.[8][9] 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.[10] The three vault proteins (MVP, VPARP, and TEP1) have each been knocked out individually and in combination (VPARP and TEP1) in mice.[11][12][13] 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.[14] The only phenotype seen in the Dictyostelium double knockout was growth retardation under nutritional stress.[15] If vaults are involved in an 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.[16] 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.[14]

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.[17]

Although vaults have been observed in many eukaryotic species, a few species do not appear to have the protein. These include:[18]

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]

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.[19] 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.[15] 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.

In 2003 a company called Vault Pharma Inc. was established to move the first vault therapeutic into a phase I clinical trial. This vault is packaged with a chemokine and will be used to activate the immune system to attack lung cancer.[20][21] Vault Pharma is currently working with Protein Sciences Corp. to develop the GLP/cGMP manufacture of this vault-based therapeutic

References

  1. ^ a b 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. doi:10.1126/science.1164975. PMID 19150846. 
  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. PMC 2114306. PMID 2943744. 
  3. ^ a b c 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. 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. 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. 
  8. ^ 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. PMID 8270627. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. PMC 2193651. PMID 11149928. 
  12. ^ 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. PMC 86427. PMID 11027287. 
  13. ^ 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. 
  14. ^ a b 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. 
  15. ^ a b 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. 
  16. ^ 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. 
  17. ^ http://pfam.sanger.ac.uk/family/PF01505 Major Vault Protein repeat Pfam family
  18. ^ 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. 
  19. ^ Mrazek, Jan; Toso, Daniel; Ryazantsev, Sergey; Zhang, Xing; Zhou, Z. Hong; Fernandez, Beatriz Campo; Kickhoefer, Valerie A.; Rome, Leonard H. (2014-11-25). "Polyribosomes are molecular 3D nanoprinters that orchestrate the assembly of vault particles". ACS nano 8 (11): 11552–11559. doi:10.1021/nn504778h. ISSN 1936-086X. PMC 4245718. PMID 25354757. 
  20. ^ Sharma, Sherven; Zhu, Li; Srivastava, Minu K.; Harris-White, Marni; Huang, Min; Lee, Jay M.; Rosen, Fran; Lee, Gina; Wang, Gerald (2013-01-01). "CCL21 Chemokine Therapy for Lung Cancer". International Trends in Immunity 1 (1): 10–15. ISSN 2326-3121. PMC 4175527. PMID 25264541. 
  21. ^ Kar, Upendra K.; Srivastava, Minu K.; Andersson, Asa; Baratelli, Felicita; Huang, Min; Kickhoefer, Valerie A.; Dubinett, Steven M.; Rome, Leonard H.; Sharma, Sherven (2011-01-01). "Novel CCL21-vault nanocapsule intratumoral delivery inhibits lung cancer growth". PloS One 6 (5): e18758. doi:10.1371/journal.pone.0018758. ISSN 1932-6203. PMC 3086906. PMID 21559281. 

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Major Vault Protein repeat Provide feedback

The vault is a ubiquitous and highly conserved ribonucleoprotein particle of approximately 13 mDa of unknown function [1]. This family corresponds to a repeat found in the amino terminal half of the major vault protein.

Literature references

  1. Kong LB, Siva AC, Rome LH, Stewart PL , Structure 1999;7:371-379.: Structure of the vault, a ubiquitous celular component. PUBMED:10196123 EPMC:10196123


This tab holds annotation information from the InterPro database.

InterPro entry IPR002499

Vaults are the largest ribonucleoprotein particles known, having a mass of approximately 13 MDa. They are multi-subunit structures that may act as scaffolds for proteins involved in signal transduction and may also play a role in nucleo-cytoplasmic transport. Vaults are present in most normal tissues, but are more highly expressed in epithelial cells with secretory and excretory functions, as well as in cells chronically exposed to xenobiotics, such as bronchial cells and cells lining the intestine [PUBMED:16918321]. Overexpression of these proteins is linked with multidrug-resistance in cancer cells.

The mammalian vault structure is highly regular and consists of approximately 96 molecules of the 100 kDa major vault protein (MVP), 2 molecules of the 240 kDa minor vault protein TEP1, 8 molecules of the 193 kDa minor vault protein VPARP and at least 6 copies of a small untranslated RNA of 88-141 bases. The MVP molecules form the core of the complex, which is a barrel-like structure with an invaginated waist and two protruding caps. The complex can unfold into two symmetrical flower-like structures with 8 petals each supposedly consisting of 6 MVP molecules [PUBMED:10196123].

The MVP protein is composed of two distinct domains [PUBMED:16373071]. The N-terminal domain contains ~8 copies of the vault repeat (or MVP repeat) in tandem. The MVP repeat is composed of ~53 amino acids and forms a structural part of the vault wall. The C-terminal part of MVP may be involved in oligomerization and be located in the vault cap, while the MVP repeats in the N-terminal part can be packed like staves in a barrel to form the vault wall. The 3D structure of the repeat forms a fold that consists of a three stranded (B) antiparallel beta-sheet in a unique topology B2-B1-B3 and two loops. MVP repeats can be interaction-mediating modules, as MVP repeats 3 and 4 bind VPARP, which is one of the other vault proteins.

Domain organisation

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Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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  Seed
(164)
Full
(555)
Representative proteomes UniProt
(988)
NCBI
(1325)
Meta
(5)
RP15
(234)
RP35
(311)
RP55
(386)
RP75
(473)
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Key: ✓ available, x not generated, not available.

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  Seed
(164)
Full
(555)
Representative proteomes UniProt
(988)
NCBI
(1325)
Meta
(5)
RP15
(234)
RP35
(311)
RP55
(386)
RP75
(473)
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  Seed
(164)
Full
(555)
Representative proteomes UniProt
(988)
NCBI
(1325)
Meta
(5)
RP15
(234)
RP35
(311)
RP55
(386)
RP75
(473)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

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HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Bateman A
Previous IDs: none
Type: Repeat
Author: Bateman A
Number in seed: 164
Number in full: 555
Average length of the domain: 42.60 aa
Average identity of full alignment: 38 %
Average coverage of the sequence by the domain: 20.41 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.0 8.3
Trusted cut-off 20.2 8.7
Noise cut-off 19.9 8.2
Model length: 42
Family (HMM) version: 15
Download: download the raw HMM for this family

Species distribution

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Interactions

There is 1 interaction for this family. More...

Vault

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Vault domain has been found. There are 187 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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