RUFY2

RUN and FYVE domain containing 2 (RUFY2) is a protein that in humans is encoded by the RUFY2 gene.^[5] 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.^[6]

RUFY2
Identifiers
Aliases	RUFY2, RABIP4R, ZFYVE13, RUN and FYVE domain containing 2
External IDs	OMIM: 610328 MGI: 1917682 HomoloGene: 23064 GeneCards: RUFY2
Gene location (Human) Chr. Chromosome 10 (human)^[1] Band 10q21.3 Start 68,341,107 bp^[1] End 68,407,294 bp^[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)^[2] Band 10 B4|10 32.51 cM Start 62,816,002 bp^[2] End 62,852,989 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon sural nerve Brodmann area 9 ganglionic eminence prefrontal cortex cingulate gyrus hypothalamus right uterine tube amygdala internal globus pallidus Top expressed in superior frontal gyrus cerebellar cortex olfactory epithelium substantia nigra supraoptic nucleus trigeminal ganglion ventral tegmental area facial motor nucleus temporal lobe neural tube More reference expression data BioGPS n/a
Gene ontology Molecular function metal ion binding SH3 domain binding Cellular component nucleus cytoplasm endosome Biological process regulation of endocytosis biological process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 55680 70432 Ensembl ENSG00000204130 ENSMUSG00000020070 UniProt Q8WXA3 Q8R4C2 RefSeq (mRNA) NM_001042417 NM_001278225 NM_017987 NM_001330103 NM_027425 RefSeq (protein) NP_001035882 NP_001265154 NP_001317032 NP_060457 NP_081701 Location (UCSC) Chr 10: 68.34 – 68.41 Mb Chr 10: 62.82 – 62.85 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

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).^[7] The gene produces a 2,080 base pair mRNA. There are 18 predicted exons in the human gene ^[8] with 13 alternative transcripts.^[9]

Gene neighborhood

8,180 base pairs upstream of RUFY2 is the protein-coding gene for phenazine biosynthesis-like protein domain containing (PBLD).^[10] While 6,770 base pairs downstream from RUFY2 is a DNA2 conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability.^[11]

Protein

 

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

The protein of RUFY2 consists of 655^[12] amino acid residues. RUFY2 protein contains a N-terminal RUN domain and a C-terminal FYVE domain with 2 coiled coil domains in between.^[13] The molecular weight of the mature protein is 70.0 kdal^[14] with an isoelectric point of 5.494.^[15] 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^[16] protein that localizes to the nucleus^[17] and to membranes of early endosomes.^[18] RUFY2 protein contains no signal peptide, no DNA/RNA binding sites, no mitochondrial targeting motifs and no peroxisomal targeting signal in the C-terminus.^[17] There is no transmembrane domain in RUFY2.^[19]

Domains

RUN domain

The RUN domain is between amino acids 45...168 and consists of the RPIP8, UNC-14, and NESCA proteins.^[6] The RUN domain has been shown to have interacting functions with GTPases in the Rap and Rab signal transduction pathways^[20] and endosomal membrane trafficking.^[6]

DUF972

Domain of unknown function that is part of a family of hypothetical bacterial sequences pfam06156.^[21] It make be linked to the YabA initiation control protein which functions as the chromosomal replication initiation control in bacteria.^[22]

PspA/IM30

The PspA/IM30 family is a negative regulator of sigma54 transcription initiation factor in bacteria.^[23]

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.^[24]

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.^[18]

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.^[25]

Other notable modification sites within the protein

• 4 Lysine acetylation sites
• 4 N-myristolation sites
• 3 N-glycosylation sites

Homology and evolution

RUFY2 has 4 paralogs: RUFY3, RUFY1, RUNDC3A, RUNDC3B.^[26]

There are 60^[27] orthologs of RUFY2 that have been identified including mammals, some birds, reptiles and fish.^[28] 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)^[29]	NCBI mRNA Accession	Sequence Similarity^[30]	Protein Length	Common Gene Name
Homo sapiens^[8]	Humans	--	AF461266	100%	606	RUFY2
Pan troglodytes^[31]	Common Chimp	6.4	XM_513483	99%	641	Predicted RUFY2
Pongo abelii^[32]	Orangutan	15.7	NM_001133232	99%	606	Predicted RUFY2
Macaca mulatta^[33]	Rhesus monkey	29.2	XM_001083568	100%	606	Predicted RUFY2
Sus scrofa^[34]	Wild Boar	94.2	XM_001928184	99%	640	Predicted: Predicted RUFY2
Mus musculus^[35]	Mouse	942.4	AF484555	95%	606	RUFY2
Gallus gallus^[36]	Chicken	301.7	XM_421568	95%	606	Predicted RUFY2
Taeniopygia guttata^[37]	Zebra Finch	295.0	XM_002190773	95%	590	RUFY2 transcript variant 2
Xenopus (Silurana) tropicalis^[38]	Western Clawed Frog	371.2	NM_001016214	77%	606	RUFY2
Danio rerio^[39]	Zebra Fish	400.1	NM_001105681	89%	602	RUFY2 transcript variant 2
Salmo salar^[40]	Salmon	427	NM_001139888	91%	427	RUFY2
Anolis carolinensis^[41]	Carolina anole	301.7	XM_003223694	91%	649	Predicted RUFY2
Drosophila melanogaster^[42]	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.^[6]

Expression

RUFY2 protein has been shown to mainly be expressed in the brain, lung, and testes while microarray expression shows RUFY2 ubiquitous expression.^[6][43][44]

References

1. GRCh38: Ensembl release 89: ENSG00000204130 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000020070 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: RUFY2 RUN and FYVE domain containing 2".
6. 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 3634510. PMID 23519112.
7. National Center for Biotechnology Information, U.S. National Library of Medicine EntrezGene reference information for RUFY2 RUN and FYVE domain containing 2 (Homo sapiens)
8. "NCBI Nucleotide: AF461266". {{cite journal}}: Cite journal requires |journal= (help)
9. "GeneCards: RUFY2".
10. "phenazine biosynthesis-like protein domain containing (PBLD)".
11. "DNA2 conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability".
12. "NCBI:Protein Q8WXA3.2".
13. 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.
14. 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 48584. PMID 1549558.
15. . Archived from the original on 2008-10-26.
16. . Archived from the original on 2004-03-18. Retrieved 2013-05-09.
17. "iPSORT".
18. 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.
19. 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
20. "RUN (IPR004012)".
21. "Family: DUF972 (PF06156)".
22. "YabA (IPR010377)".
23. "pfam04012: PspA_IM30".
24. "cd00065:FYVE".
25. 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 1538847. PMID 16845026.{{cite journal}}: CS1 maint: multiple names: authors list (link)
26. "Gene:RUFY2".
27. "EBI:RUFY2".
28. 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 168907. PMID 12824352.
29. "Time Tree".
30. "NCBI BLAST". {{cite journal}}: Cite journal requires |journal= (help)
31. "NCBI Nucleotide: XM_003312585". {{cite journal}}: Cite journal requires |journal= (help)
32. "NCBI Nucleotide: NM_001133232". {{cite journal}}: Cite journal requires |journal= (help)
33. "NCBI Nucleotide: XM_001083568". {{cite journal}}: Cite journal requires |journal= (help)
34. "NCBI Nucleotide: XM_003127928". {{cite journal}}: Cite journal requires |journal= (help)
35. "NCBI Nucleotide: AF484555". {{cite journal}}: Cite journal requires |journal= (help)
36. "NCBI Nucleotide: XM_421568". {{cite journal}}: Cite journal requires |journal= (help)
37. "NCBI Nucleotide: XM_002190773". {{cite journal}}: Cite journal requires |journal= (help)
38. "NCBI Nucleotide: NM_001016214". {{cite journal}}: Cite journal requires |journal= (help)
39. "NCBI Nucleotide: NM_001105681". {{cite journal}}: Cite journal requires |journal= (help)
40. "NCBI Nucleotide: NM_001139888". {{cite journal}}: Cite journal requires |journal= (help)
41. "NCBI Nucleotide: XM_003223694". {{cite journal}}: Cite journal requires |journal= (help)
42. "NCBI Nucleotide: NM_170324". {{cite journal}}: Cite journal requires |journal= (help)
43. 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 1635650. PMID 17098871.
44. "RUFY2 Expression".