{{Short description|Protein-coding gene in humans}} {{cs1 config|name-list-style=vanc}} {{Infobox_gene}} '''RUN and FYVE domain containing 2''' ('''RUFY2''') is a protein that in humans is encoded by the ''RUFY2'' gene.<ref name="entrez">{{cite web | title = Entrez Gene: RUFY2 RUN and FYVE domain containing 2| url = https://www.ncbi.nlm.nih.gov/gene?LinkName=nuccore_gene&from_uid=18266357}}</ref> 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.<ref name="KitagishiMatsuda2013">{{cite journal|last1=Kitagishi|first1=Yasuko|last2=Matsuda|first2=Satoru|title=RUFY, Rab and Rap Family Proteins Involved in a Regulation of Cell Polarity and Membrane Trafficking|journal=International Journal of Molecular Sciences|volume=14|issue=3|year=2013|pages=6487–6498|issn=1422-0067|doi=10.3390/ijms14036487|pmid=23519112|pmc=3634510|doi-access=free}}</ref>
== Gene == thumb|center|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) [http://genome.ucsc.edu/cgi-bin/hgTracks?hgsid=335550399 (map)].<ref>National Center for Biotechnology Information, U.S. National Library of Medicine [https://www.ncbi.nlm.nih.gov/gene/55680 EntrezGene reference information for RUFY2 RUN and FYVE domain containing 2 (Homo sapiens)]</ref> The gene produces a 2,080 base pair mRNA. There are 18 predicted exons in the human gene <ref name="Nucleotide: Hsa"/> with 13 alternative transcripts.<ref name="GeneCards">{{cite web | title = GeneCards: RUFY2| url =https://www.genecards.org/cgi-bin/carddisp.pl?gene=RUFY2&search=RUFY2}}</ref>
=== Gene neighborhood === 8,180 base pairs upstream of RUFY2 is the protein-coding gene for phenazine biosynthesis-like protein domain containing (PBLD).<ref name="Phenazine biosynthesis-like protein">{{cite web | title = phenazine biosynthesis-like protein domain containing (PBLD)| url=http://genome.ucsc.edu/cgi-bin/hgGene?hgg_gene=uc001jns.1&hgg_prot=P30039&hgg_chrom=chr10&hgg_start=70042416&hgg_end=70092684&hgg_type=knownGene&db=hg19&hgsid=335785853}}</ref> While 6,770 base pairs downstream from RUFY2 is a DNA2 conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability.<ref name="DNA2 conserved helicase/nuclease">{{cite web | title = DNA2 conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability| url=http://genome.ucsc.edu/cgi-bin/hgGene?hgg_gene=uc021prt.1&hgg_prot=P51530&hgg_chrom=chr10&hgg_start=70173820&hgg_end=70231879&hgg_type=knownGene&db=hg19&hgsid=335785853}}</ref>
== Protein ==
thumb|Features of the RUFY2 protein depicting the RUN, DUF972, PspA_IM30 and FYVE domains. The protein of RUFY2 consists of 655<ref name="NCBI:Protein Q8WXA3.2">{{cite web | title = NCBI:Protein Q8WXA3.2| url=https://www.ncbi.nlm.nih.gov/protein/Q8WXA3.2}}</ref> amino acid residues. RUFY2 protein contains a N-terminal RUN domain and a C-terminal FYVE domain with 2 coiled coil domains in between.<ref name="pmid18029348">{{cite journal |vauthors=Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Björling E, Asplund A, Pontén F, Brismar H, Uhlén M, Andersson-Svahn H | title = Toward a confocal subcellular atlas of the human proteome | journal = Mol. Cell. Proteomics | volume = 7 | issue = 3 | pages = 499–508 |date=March 2008 | pmid = 18029348 | doi = 10.1074/mcp.M700325-MCP200 | doi-access = free }}</ref> The molecular weight of the mature protein is 70.0 kdal<ref name="Molecular Weight">{{cite journal |vauthors=Brendel V, Bucher P, Nourbakhsh IR, Blaisdell BE, Karlin S | title = Methods and algorithms for statistical analysis of protein sequences | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 89 | issue = 6 | pages = 2002–6 |date=March 1992 | pmid = 1549558 | pmc = 48584 | doi = 10.1073/pnas.89.6.2002| bibcode = 1992PNAS...89.2002B | doi-access = free }}</ref> with an isoelectric point of 5.494.<ref name="Isoelectric Point">{{cite web| title = Gateway to Isoelectric Point Service| url = http://www.embl-heidelberg.de/cgi/pi-wrapper.pl| url-status = dead| archive-url = https://web.archive.org/web/20081026062821/http://www.embl-heidelberg.de/cgi/pi-wrapper.pl| archive-date = 2008-10-26}}</ref> 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<ref name="SOSUI">{{cite web| title = SOSUI hydrophobicity| url = http://bp.nuap.nagoya-u.ac.jp/sosui/| access-date = 2013-05-09| archive-date = 2004-03-18| archive-url = https://web.archive.org/web/20040318022546/http://bp.nuap.nagoya-u.ac.jp/sosui/| url-status = dead}}</ref> protein that localizes to the nucleus<ref name="iPSORT">{{cite web | title = iPSORT| url=http://ipsort.hgc.jp/}}</ref> and to membranes of early endosomes.<ref name="Yang2002">{{cite journal |vauthors=Yang J, Kim O, Wu J, Qiu Y | title = 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 | journal = J. Biol. Chem. | volume = 277 | issue = 33 | pages = 30219–26 |date=August 2002 | pmid = 11877430 | doi = 10.1074/jbc.M111933200 | doi-access = free }}</ref> RUFY2 protein contains no signal peptide, no DNA/RNA binding sites, no mitochondrial targeting motifs and no peroxisomal targeting signal in the C-terminus.<ref name="iPSORT"/> There is no transmembrane domain in RUFY2.<ref name="Transmembrane helix">{{Citation |last1= Glasgow |first1= Ed |last2= Littlejohn |first2= T. |last3= Major |first3= F. |last4= Lathrop |first4=R. |last5= Sankoff |first5= R. |last6= Sensen |first6= C. |year=1998 |title= A hidden Markov model for predicting transmembrane helices in protein sequences |publisher= AAAI Press |location= Menlo Park, CA |pages= 175–182 |url=http://www.cbs.dtu.dk/services/TMHMM-2.0 }}</ref>
=== Domains ===
=== RUN domain ===
The RUN domain is between amino acids 45...168 and consists of the RPIP8, UNC-14, and NESCA proteins.<ref name="KitagishiMatsuda2013"/> The RUN domain has been shown to have interacting functions with GTPases in the Rap and Rab signal transduction pathways<ref name="InterPro">{{cite web | title = RUN (IPR004012)| url=http://www.ebi.ac.uk/interpro/entry/IPR004012}}</ref> and endosomal membrane trafficking.<ref name="KitagishiMatsuda2013"/>
=== DUF972 ===
Domain of unknown function that is part of a family of hypothetical bacterial sequences pfam06156.<ref name ="Pfam">{{cite web | title = Family: DUF972 (PF06156)| url=http://pfam.sanger.ac.uk/family/PF06156}}</ref> It make be linked to the YabA initiation control protein which functions as the chromosomal replication initiation control in bacteria.<ref name="EBI-InterPro">{{cite web | title = YabA (IPR010377)| url=http://www.ebi.ac.uk/interpro/entry/IPR010377}}</ref>
=== PspA/IM30 ===
The PspA/IM30 family is a negative regulator of sigma54 transcription initiation factor in bacteria.<ref name="NCBI Conserved Domains">{{cite web | title = pfam04012: PspA_IM30| url=https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=112811}}</ref>
=== 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.<ref name="Conserved Domains">{{cite web | title = cd00065:FYVE| url=https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=238022}}</ref>
=== 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.<ref name="Yang2002"/>
=== Post-translational modifications === thumb|right|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.<ref>{{Cite journal | author = Edouard de Castro, Christian J. A. Sigrist, Alexandre Gattiker, Virginie Bulliard, Petra S. Langendijk-Genevaux, Elisabeth Gasteiger, Amos Bairoch & Nicolas Hulo | title = ScanProsite: detection of PROSITE signature matches and ProRule-associated functional and structural residues in proteins | journal = Nucleic Acids Research | volume = 34 | issue = Web Server issue | pages = W362–W365 |date=July 2006 | doi = 10.1093/nar/gkl124 | pmid = 16845026 | pmc=1538847 }}</ref>
==== 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.<ref name="Ensembl">{{cite web | title = Gene:RUFY2| url=https://www.ebi.ac.uk/s4/jump?from=aHR0cDovL3d3dy5lYmkuYWMudWsvczQvc3VtbWFyeS9tb2xlY3VsYXIvZ2VuZT90ZXJtPVJVRlkyJmNsYXNzaWZpY2F0aW9uPTk2MDYmdGlkPW5hbWVPcmdFTlNHMDAwMDAyMDQxMzA%3D&hash=2D884&url=http://www.ensembl.org/Homo_sapiens/Gene/Compara_Paralog?g%3DENSG00000204130%3Bdb%3Dcore}}</ref>
There are 60<ref name="EMBL-EBI">{{cite web | title = EBI:RUFY2| url=https://www.ebi.ac.uk/s4/summary/molecular/gene?term=RUFY2&classification=9606&tid=nameOrgENSG00000204130}}</ref> orthologs of RUFY2 that have been identified including mammals, some birds, reptiles and fish.<ref name="pmid12824352">{{cite journal |vauthors=Chenna R, Sugawara H, Koike T, Lopez R, Gibson TJ, Higgins DG, Thompson JD | title = Multiple sequence alignment with the Clustal series of programs | journal = Nucleic Acids Res. | volume = 31 | issue = 13 | pages = 3497–500 |date=July 2003 | pmid = 12824352 | pmc = 168907 | doi = 10.1093/nar/gkg500}}</ref> 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. {| class="wikitable sortable" |- ! Genus Species !! Organism Common Name !! Divergence from Humans (MYA)<ref name="Time Tree">{{cite web | title = Time Tree| url =http://www.timetree.org/}}</ref> !! NCBI mRNA Accession !! Sequence Similarity<ref name="BLAST">{{cite journal | title = NCBI BLAST| url =https://blast.ncbi.nlm.nih.gov/Blast.cgi}}</ref> !! Protein Length !! Common Gene Name |- | ''Homo sapiens''<ref name="Nucleotide: Hsa">{{cite journal | title = NCBI Nucleotide: AF461266| date =12 August 2002| url =https://www.ncbi.nlm.nih.gov/nuccore/AF461266.1}}</ref> || Humans || -- || AF461266 || 100% || 606 || RUFY2 |- | ''Pan troglodytes''<ref name="Nucleotide: Ptr">{{cite journal | title = NCBI Nucleotide: XM_003312585| date =25 October 2012| url =https://www.ncbi.nlm.nih.gov/nuccore/XM_003312585.1}}</ref> || Common Chimp || 6.4 || XM_513483 || 99% || 641 || Predicted RUFY2 |- | ''Pongo abelii''<ref name="Nucleotide: Pab">{{cite journal | title = NCBI Nucleotide: NM_001133232| date =26 March 2023| url =https://www.ncbi.nlm.nih.gov/nuccore/NM_001133232.1}}</ref> || Orangutan || 15.7 || NM_001133232 || 99% || 606 || Predicted RUFY2 |- | ''Macaca mulatta''<ref name="Nucleotide: Mfa">{{cite journal | title = NCBI Nucleotide: XM_001083568| date =June 2010| url =https://www.ncbi.nlm.nih.gov/nuccore/XM_001083568.2}}</ref> || Rhesus monkey || 29.2 || XM_001083568 || 100% || 606 || Predicted RUFY2 |- | ''Sus scrofa''<ref name="Nucleotide: Ssu">{{cite journal | title = NCBI Nucleotide: XM_003127928| date =5 November 2010| url =https://www.ncbi.nlm.nih.gov/nuccore/XM_001928184.1}}</ref>|| Wild Boar || 94.2 || XM_001928184 || 99% || 640 || Predicted: Predicted RUFY2 |- | ''Mus musculus''<ref name="Nucleotide: Mmu">{{cite journal | title = NCBI Nucleotide: AF484555| date =24 April 2002| url =https://www.ncbi.nlm.nih.gov/nuccore/AF484555.1}}</ref>|| Mouse || 942.4 || AF484555 || 95% || 606 || RUFY2 |- | ''Gallus gallus''<ref name="Nucleotide: Gga">{{cite journal | title = NCBI Nucleotide: XM_421568| date =16 December 2011| url =https://www.ncbi.nlm.nih.gov/nuccore/XM_421568.3}}</ref> || Chicken || 301.7 || XM_421568 || 95% || 606 || Predicted RUFY2 |- | ''Taeniopygia guttata''<ref name="Nucleotide: Tgu">{{cite journal | title = NCBI Nucleotide: XM_002190773| date =12 February 2013| url =https://www.ncbi.nlm.nih.gov/nuccore/XM_002190773.2}}</ref> || Zebra Finch || 295.0 || XM_002190773 || 95% || 590 || RUFY2 transcript variant 2 |- | ''Xenopus (Silurana) tropicalis''<ref name="Nucleotide: Xtr">{{cite journal | title = NCBI Nucleotide: NM_001016214 | date =22 December 2019| url =https://www.ncbi.nlm.nih.gov/nuccore/NM_001016214.2}}</ref> || Western Clawed Frog || 371.2 || NM_001016214 || 77% || 606 || RUFY2 |- | ''Danio rerio''<ref name="Nucleotide: Dre">{{cite journal | title = NCBI Nucleotide: NM_001105681 | date =6 August 2017| url =https://www.ncbi.nlm.nih.gov/nuccore/NM_001105681.2}}</ref> || Zebra Fish || 400.1 || NM_001105681 || 89% || 602 || RUFY2 transcript variant 2 |- | ''Salmo salar''<ref name="Nucleotide: Ssa">{{cite journal | title = NCBI Nucleotide: NM_001139888 | date =12 January 2022| url =https://www.ncbi.nlm.nih.gov/nuccore/NM_001139888.1}}</ref> || Salmon || 427 || NM_001139888 || 91% || 427 || RUFY2 |- | ''Anolis carolinensis''<ref name="Nucleotide: Nve">{{cite journal | title = NCBI Nucleotide: XM_003223694 | date =30 March 2011| url =https://www.ncbi.nlm.nih.gov/nuccore/XM_003223694.1}}</ref> || Carolina anole || 301.7 || XM_003223694 || 91% || 649 || Predicted RUFY2 |- | ''Drosophila melanogaster''<ref name="Nucleotide: Cqu">{{cite journal | title = NCBI Nucleotide: NM_170324 | date =16 January 2013| url =https://www.ncbi.nlm.nih.gov/nuccore/NM_170324.2}}</ref> || Fruit fly || 782.7 || NM_170324 || 63% || 729 || CG31064 |} thumb|center|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.<ref name="KitagishiMatsuda2013"/>
== Expression ==
RUFY2 protein has been shown to mainly be expressed in the brain, lung, and testes while microarray expression shows RUFY2 ubiquitous expression.<ref name="KitagishiMatsuda2013"/><ref name="MajercakRay2006">{{cite journal |vauthors=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 | title = LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 47 | pages = 17967–72 |date=November 2006 | pmid = 17098871 | pmc = 1635650 | doi = 10.1073/pnas.0605461103 | bibcode = 2006PNAS..10317967M | doi-access = free }}</ref><ref name="Microarray expression">{{cite web | title = RUFY2 Expression | url=http://biogps.org/#goto=genereport&id=55680}}</ref>
== References == {{Reflist|35em}}
Category:Protein domains