RUFY2

RUFY2
Identifiers
Aliases RUFY2, RABIP4R, ZFYVE13, RUN and FYVE domain containing 2
External IDs MGI: 1917682 HomoloGene: 23064 GeneCards: RUFY2
Orthologs
Species Human Mouse
Entrez

55680

70432

Ensembl

ENSG00000204130

ENSMUSG00000020070

UniProt

Q8WXA3
Q5TC51

Q8R4C2

RefSeq (mRNA)

NM_001042417
NM_001278225
NM_017987

NM_027425

RefSeq (protein)

NP_001035882.1
NP_001265154.1
NP_060457.4

NP_081701.2

Location (UCSC) Chr 10: 68.34 – 68.41 Mb Chr 10: 62.98 – 63.02 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

RUN and FYVE domain containing 2 (RUFY2) is a protein that in humans is encoded by the RUFY2 gene.[3] The RUFY2 gene is named for two of its domains, the RUN domain and FYVE domains. RUFY2 is a member of the RUFY family of proteins that include RUFY1, RUFY2, RUFY3, and RUFY4. RUFY2 protein has a dynamic role in endosomal membrane trafficking.[4]

Gene

Homo sapiens Chromosome 10 with RUFY2 gene highlighted in red

The human RUFY2 gene is located on the long (q) arm of chromosome 10 at region 21 band 3, from base pair 70,100,864 to base pair 70,167,051 on the reverse strand (Build GRCh37/hg19) (map).[5] The gene produces a 2,080 base pair mRNA. There are 18 predicted exons in the human gene [6] with 13 alternative transcripts.[7]

Gene Neighborhood

8,180 base pairs upstream of RUFY2 is the protein-coding gene for phenazine biosynthesis-like protein domain containing (PBLD).[8] While 6,770 base pairs downstream from RUFY2 is a DNA2 conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability.[9]

Protein

Features of the RUFY2 protein depicting the RUN, DUF972, PspA_IM30 and FYVE domains.

The protein of RUFY2 consists of 655[10] amino acid residues. RUFY2 protein contains a N-terminal RUN domain and a C-terminal FYVE domain with 2 coiled coil domains in between.[11] The molecular weight of the mature protein is 70.0 kdal[12] with an isoelectric point of 5.494.[13] PHYRE2 protein tertiary structure tool suggests that RUFY2 has 15 alpha helices and the longest helix spanning amino acids 199...512 as seen in the figure to the right. RUFY2 is a soluble[14] protein that localizes to the nucleus[15] and to membranes of early endosomes.[16] RUFY2 protein contains no signal peptide, no DNA/RNA binding sites, no mitochondrial targeting motifs and no peroxisomal targeting signal in the C-terminus.[15] There is no transmembrane domain in RUFY2.[17]

RUN domain

The RUN domain is between amino acids 45...168 and consists of the RPIP8, UNC-14, and NESCA proteins.[4] The RUN domain has been shown to have interacting functions with GTPases in the Rap and Rab signal transduction pathways[18] and endosomal membrane trafficking.[4]

DUF972

Domain of unknown function that is part of a family of hypothetical bacterial sequences pfam06156.[19] It make be linked to the YabA initiation control protein which functions as the chromosomal replication initiation control in bacteria.[20]

PspA/IM30

The PspA/IM30 family is a negative regulator of sigma54 transcription initiation factor in bacteria.[21]

FYVE domain

FYVE domain consists of Fab-1, YGL023, Vps27, and EEA1 proteins. Within the FYVE domain there are Zinc finger binding sites that interact with phosphatidylinositol-3-phosphate, to bring target proteins to membrane lipids.[22]

Protein Interactions

The proline rich motif in the FYVE domain of RUFY2 has been shown to have binding activity with the SH3 domain of EPHA3 (Etk) in signal transduction pathways.[16]

Post-translational Modifications

Modification sites on RUFY2 protein

RUFY2 possibly has 6 phosphorylation sites and are located mainly in the DUF972 region. RUFY2 also has 6 protein kinase C phosphorylation sites that are located mainly within the FYVE domain.[23]

Other notable modification sites within the protein

Homology and Evolution

RUFY2 has 4 paralogs: RUFY3, RUFY1, RUNDC3A, RUNDC3B.[24]

There are 60[25] orthologs of RUFY2 that have been identified including mammals, some birds, reptiles and fish.[26] RUFY2 is highly conserved among its orthologs but is not present in plants, bacteria, archea or protist.

Species Distribution

The following table lists the homologs of RUFY2.

Genus Species Organism Common Name Divergence from Humans (MYA) [27] NCBI mRNA Accession Sequence Similarity [28] Protein Length Common Gene Name
Homo sapiens[6] Humans -- AF461266 100% 606 RUFY2
Pan troglodytes[29] Common Chimp 6.4 XM_513483 99% 641 Predicted RUFY2
Pongo abelii [30] Orangutan 15.7 NM_001133232 99% 606 Predicted RUFY2
Macaca mulatta [31] Rhesus monkey 29.2 XM_001083568 100% 606 Predicted RUFY2
Sus scrofa [32] Wild Boar 94.2 XM_001928184 99% 640 Predicted: Predicted RUFY2
Mus musculus [33] Mouse 942.4 AF484555 95% 606 RUFY2
Gallus gallus [34] Chicken 301.7 XM_421568 95% 606 Predicted RUFY2
Taeniopygia guttata [35] Zebra Finch 295.0 XM_002190773 95% 590 RUFY2 transcript variant 2
Xenopus (Silurana) tropicalis [36] Western Clawed Frog 371.2 NM_001016214 77% 606 RUFY2
Danio rerio [37] Zebra Fish 400.1 NM_001105681 89% 602 RUFY2 transcript variant 2
Salmo salar [38] Salmon 427 NM_001139888 91% 427 RUFY2
Anolis carolinensis [39] Carolina anole 301.7 XM_003223694 91% 649 Predicted RUFY2
Drosophila melanogaster [40] Fruit fly 782.7 NM_170324 63% 729 CG31064
Unrooted phylogenetic tree of RUFY2 protein

Clinical Significance

Certain neurodegenerative diseases such as Alzheimer's have been found to have defective endosomal trafficking. Therefore, the involvement of RUFY2 protein domains, RUN and FYVE, may possibly play a role in neurodegenerative diseases such as Alzheimer’s.[4]

Expression

RUFY2 protein has been shown to mainly be expressed in the brain, lung, and testes while microarray expression shows RUFY2 ubiquitous expression.[4][41][42]

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. ↑ "Entrez Gene: RUFY2 RUN and FYVE domain containing 2".
  4. 1 2 3 4 5 Kitagishi, Yasuko; Matsuda, Satoru (2013). "RUFY, Rab and Rap Family Proteins Involved in a Regulation of Cell Polarity and Membrane Trafficking". International Journal of Molecular Sciences. 14 (3): 6487–6498. doi:10.3390/ijms14036487. ISSN 1422-0067. PMC 3634510Freely accessible. PMID 23519112.
  5. ↑ National Center for Biotechnology Information, U.S. National Library of Medicine EntrezGene reference information for RUFY2 RUN and FYVE domain containing 2 (Homo sapiens)
  6. 1 2 "NCBI Nucleotide: AF461266".
  7. ↑ "GeneCards: RUFY2".
  8. ↑ "phenazine biosynthesis-like protein domain containing (PBLD)".
  9. ↑ "DNA2 conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability".
  10. ↑ "NCBI:Protein Q8WXA3.2".
  11. ↑ Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Björling E, Asplund A, Pontén F, Brismar H, Uhlén M, Andersson-Svahn H (March 2008). "Toward a confocal subcellular atlas of the human proteome". Mol. Cell Proteomics. 7 (3): 499–508. doi:10.1074/mcp.M700325-MCP200. PMID 18029348.
  12. ↑ Brendel V, Bucher P, Nourbakhsh IR, Blaisdell BE, Karlin S (March 1992). "Methods and algorithms for statistical analysis of protein sequences". Proc. Natl. Acad. Sci. U.S.A. 89 (6): 2002–6. Bibcode:1992PNAS...89.2002B. doi:10.1073/pnas.89.6.2002. PMC 48584Freely accessible. PMID 1549558.
  13. ↑ "Gateway to Isoelectric Point Service".
  14. ↑ "SOSUI hydrophobicity".
  15. 1 2 "iPSORT".
  16. 1 2 Yang J, Kim O, Wu J, Qiu Y (August 2002). "Interaction between tyrosine kinase Etk and a RUN domain- and FYVE domain-containing protein RUFY1. A possible role of ETK in regulation of vesicle trafficking". J. Biol. Chem. 277 (33): 30219–26. doi:10.1074/jbc.M111933200. PMID 11877430.
  17. ↑ Glasgow, Ed; Littlejohn, T.; Major, F.; Lathrop, R.; Sankoff, R.; Sensen, C. (1998), A hidden Markov model for predicting transmembrane helices in protein sequences, Menlo Park, CA: AAAI Press, pp. 175–182
  18. ↑ "RUN (IPR004012)".
  19. ↑ "Family: DUF972 (PF06156)".
  20. ↑ "YabA (IPR010377)".
  21. ↑ "pfam04012: PspA_IM30".
  22. ↑ "cd00065:FYVE".
  23. ↑ Edouard de Castro, Christian J. A. Sigrist, Alexandre Gattiker, Virginie Bulliard, Petra S. Langendijk-Genevaux, Elisabeth Gasteiger, Amos Bairoch & Nicolas Hulo (July 2006). "ScanProsite: detection of PROSITE signature matches and ProRule-associated functional and structural residues in proteins". Nucleic acids research. 34 (Web Server issue): W362–W365. doi:10.1093/nar/gkl124. PMC 1538847Freely accessible. PMID 16845026.
  24. ↑ "Gene:RUFY2".
  25. ↑ "EBI:RUFY2".
  26. ↑ Chenna R, Sugawara H, Koike T, Lopez R, Gibson TJ, Higgins DG, Thompson JD (July 2003). "Multiple sequence alignment with the Clustal series of programs". Nucleic Acids Res. 31 (13): 3497–500. doi:10.1093/nar/gkg500. PMC 168907Freely accessible. PMID 12824352.
  27. ↑ "Time Tree".
  28. ↑ "NCBI BLAST".
  29. ↑ "NCBI Nucleotide: XM_003312585".
  30. ↑ "NCBI Nucleotide: NM_001133232".
  31. ↑ "NCBI Nucleotide: XM_001083568".
  32. ↑ "NCBI Nucleotide: XM_003127928".
  33. ↑ "NCBI Nucleotide: AF484555".
  34. ↑ "NCBI Nucleotide: XM_421568".
  35. ↑ "NCBI Nucleotide: XM_002190773".
  36. ↑ "NCBI Nucleotide: NM_001016214".
  37. ↑ "NCBI Nucleotide: NM_001105681".
  38. ↑ "NCBI Nucleotide: NM_001139888".
  39. ↑ "NCBI Nucleotide: XM_003223694".
  40. ↑ "NCBI Nucleotide: NM_170324".
  41. ↑ Majercak J, Ray WJ, Espeseth A, Simon A, Shi XP, Wolffe C, Getty K, Marine S, Stec E, Ferrer M, Strulovici B, Bartz S, Gates A, Xu M, Huang Q, Ma L, Shughrue P, Burchard J, Colussi D, Pietrak B, Kahana J, Beher D, Rosahl T, Shearman M, Hazuda D, Sachs AB, Koblan KS, Seabrook GR, Stone DJ (November 2006). "LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease". Proc. Natl. Acad. Sci. U.S.A. 103 (47): 17967–72. Bibcode:2006PNAS..10317967M. doi:10.1073/pnas.0605461103. PMC 1635650Freely accessible. PMID 17098871.
  42. ↑ "RUFY2 Expression".
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