RHBL2_HUMAN
ID RHBL2_HUMAN Reviewed; 303 AA.
AC Q9NX52; B2RNT3; B9EH75; Q6P175; Q8NER8; Q96E02;
DT 05-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-2005, sequence version 2.
DT 03-AUG-2022, entry version 163.
DE RecName: Full=Rhomboid-related protein 2;
DE Short=RRP2;
DE EC=3.4.21.105;
DE AltName: Full=Rhomboid-like protein 2;
DE Contains:
DE RecName: Full=Rhomboid-related protein 2, N-terminal fragment;
DE Short=NTF;
DE Contains:
DE RecName: Full=Rhomboid-related protein 2, C-terminal fragment;
DE Short=CTF;
GN Name=RHBDL2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Jiao W., Yuan W., Wu X.;
RT "Cloning and characterization of RHBDL2, a novel rhomboid-like gene, in
RT human development.";
RL Submitted (JUN-2002) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Adrenal cortex, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 11-303 (ISOFORM 1).
RC TISSUE=Gastric carcinoma;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP FUNCTION, AND MUTAGENESIS OF TRP-121; ARG-122; ASN-139; GLY-185; SER-187
RP AND HIS-250.
RX PubMed=11672525; DOI=10.1016/s0092-8674(01)00525-6;
RA Urban S., Lee J.R., Freeman M.;
RT "Drosophila Rhomboid-1 defines a family of putative intramembrane serine
RT proteases.";
RL Cell 107:173-182(2001).
RN [6]
RP FUNCTION, AND MUTAGENESIS OF SER-187.
RX PubMed=15047175; DOI=10.1016/j.bbrc.2004.03.039;
RA Pascall J.C., Brown K.D.;
RT "Intramembrane cleavage of ephrinB3 by the human rhomboid family protease,
RT RHBDL2.";
RL Biochem. Biophys. Res. Commun. 317:244-252(2004).
RN [7]
RP CATALYTIC ACTIVITY, PROTEOLYTIC PROCESSING, MUTAGENESIS OF TRP-121 AND
RP ARG-122, AND SUBCELLULAR LOCATION.
RX PubMed=19850051; DOI=10.1016/j.jmb.2009.10.025;
RA Lei X., Li Y.M.;
RT "The processing of human rhomboid intramembrane serine protease RHBDL2 is
RT required for its proteolytic activity.";
RL J. Mol. Biol. 394:815-825(2009).
CC -!- FUNCTION: Involved in regulated intramembrane proteolysis and the
CC subsequent release of functional polypeptides from their membrane
CC anchors. Known substrate: EFNB3. {ECO:0000269|PubMed:11672525,
CC ECO:0000269|PubMed:15047175}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Cleaves type-1 transmembrane domains using a catalytic dyad
CC composed of serine and histidine that are contributed by different
CC transmembrane domains.; EC=3.4.21.105;
CC Evidence={ECO:0000269|PubMed:19850051};
CC -!- INTERACTION:
CC Q9NX52-3; Q969S0: SLC35B4; NbExp=3; IntAct=EBI-12908426, EBI-10281213;
CC Q9NX52-3; P55061: TMBIM6; NbExp=3; IntAct=EBI-12908426, EBI-1045825;
CC -!- SUBCELLULAR LOCATION: [Rhomboid-related protein 2, C-terminal
CC fragment]: Cell membrane {ECO:0000269|PubMed:19850051}; Multi-pass
CC membrane protein {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9NX52-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NX52-3; Sequence=VSP_012692;
CC -!- PTM: Proteolytic processing of the proenzyme produces a N-terminal
CC fragment (NTF) and a C-terminal fragment (CTF). The processing is
CC required for activation of the protease. {ECO:0000269|PubMed:19850051}.
CC -!- MISCELLANEOUS: [Isoform 2]: May be due to an intron retention.
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the peptidase S54 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH13103.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAA91168.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AY126343; AAM95697.1; -; mRNA.
DR EMBL; AL139260; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC013103; AAH13103.1; ALT_INIT; mRNA.
DR EMBL; BC137108; AAI37109.1; -; mRNA.
DR EMBL; BC137110; AAI37111.1; -; mRNA.
DR EMBL; AK000442; BAA91168.1; ALT_INIT; mRNA.
DR CCDS; CCDS30680.1; -. [Q9NX52-1]
DR RefSeq; NP_060291.2; NM_017821.4. [Q9NX52-1]
DR AlphaFoldDB; Q9NX52; -.
DR SMR; Q9NX52; -.
DR BioGRID; 120273; 5.
DR IntAct; Q9NX52; 3.
DR STRING; 9606.ENSP00000289248; -.
DR MEROPS; S54.002; -.
DR iPTMnet; Q9NX52; -.
DR PhosphoSitePlus; Q9NX52; -.
DR BioMuta; RHBDL2; -.
DR DMDM; 59800189; -.
DR jPOST; Q9NX52; -.
DR MassIVE; Q9NX52; -.
DR MaxQB; Q9NX52; -.
DR PaxDb; Q9NX52; -.
DR PeptideAtlas; Q9NX52; -.
DR PRIDE; Q9NX52; -.
DR ProteomicsDB; 83039; -. [Q9NX52-1]
DR ProteomicsDB; 83040; -. [Q9NX52-3]
DR Antibodypedia; 31843; 96 antibodies from 24 providers.
DR DNASU; 54933; -.
DR Ensembl; ENST00000289248.6; ENSP00000289248.2; ENSG00000158315.11. [Q9NX52-1]
DR Ensembl; ENST00000372990.6; ENSP00000362081.1; ENSG00000158315.11. [Q9NX52-1]
DR Ensembl; ENST00000540558.1; ENSP00000441097.1; ENSG00000158315.11. [Q9NX52-3]
DR GeneID; 54933; -.
DR KEGG; hsa:54933; -.
DR MANE-Select; ENST00000372990.6; ENSP00000362081.1; NM_017821.5; NP_060291.2.
DR UCSC; uc001ccu.1; human. [Q9NX52-1]
DR CTD; 54933; -.
DR DisGeNET; 54933; -.
DR GeneCards; RHBDL2; -.
DR HGNC; HGNC:16083; RHBDL2.
DR HPA; ENSG00000158315; Tissue enhanced (esophagus).
DR MIM; 608962; gene.
DR neXtProt; NX_Q9NX52; -.
DR OpenTargets; ENSG00000158315; -.
DR PharmGKB; PA34383; -.
DR VEuPathDB; HostDB:ENSG00000158315; -.
DR eggNOG; KOG2289; Eukaryota.
DR GeneTree; ENSGT00940000159442; -.
DR HOGENOM; CLU_048023_0_0_1; -.
DR InParanoid; Q9NX52; -.
DR OMA; VCCDQLM; -.
DR PhylomeDB; Q9NX52; -.
DR TreeFam; TF313540; -.
DR BRENDA; 3.4.21.105; 2681.
DR PathwayCommons; Q9NX52; -.
DR SignaLink; Q9NX52; -.
DR BioGRID-ORCS; 54933; 13 hits in 1063 CRISPR screens.
DR ChiTaRS; RHBDL2; human.
DR GenomeRNAi; 54933; -.
DR Pharos; Q9NX52; Tbio.
DR PRO; PR:Q9NX52; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q9NX52; protein.
DR Bgee; ENSG00000158315; Expressed in mucosa of sigmoid colon and 141 other tissues.
DR Genevisible; Q9NX52; HS.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR Gene3D; 1.20.1540.10; -; 1.
DR InterPro; IPR022764; Peptidase_S54_rhomboid_dom.
DR InterPro; IPR017213; Peptidase_S54_rhomboid_met.
DR InterPro; IPR035952; Rhomboid-like_sf.
DR Pfam; PF01694; Rhomboid; 1.
DR PIRSF; PIRSF037470; Rhomboid; 1.
DR SUPFAM; SSF144091; SSF144091; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Hydrolase; Membrane; Protease;
KW Reference proteome; Serine protease; Transmembrane; Transmembrane helix.
FT CHAIN 1..303
FT /note="Rhomboid-related protein 2"
FT /id="PRO_0000206176"
FT CHAIN 1..?
FT /note="Rhomboid-related protein 2, N-terminal fragment"
FT /id="PRO_0000408510"
FT CHAIN ?..303
FT /note="Rhomboid-related protein 2, C-terminal fragment"
FT /id="PRO_0000408509"
FT TRANSMEM 72..92
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 128..148
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 159..179
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 183..203
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 212..232
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 245..265
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 278..298
FT /note="Helical"
FT /evidence="ECO:0000255"
FT REGION 20..39
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 187
FT /note="Nucleophile"
FT ACT_SITE 250
FT VAR_SEQ 133..303
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_012692"
FT VARIANT 273
FT /note="L -> M (in dbSNP:rs2147914)"
FT /id="VAR_020328"
FT MUTAGEN 121
FT /note="W->A: Reduces protease activity."
FT /evidence="ECO:0000269|PubMed:11672525,
FT ECO:0000269|PubMed:19850051"
FT MUTAGEN 122
FT /note="R->A: Abolishes protease activity, prevents
FT processing and alters localization to the plasma membrane
FT of N-terminal fragment."
FT /evidence="ECO:0000269|PubMed:11672525,
FT ECO:0000269|PubMed:19850051"
FT MUTAGEN 139
FT /note="N->A: Reduces protease activity."
FT /evidence="ECO:0000269|PubMed:11672525"
FT MUTAGEN 185
FT /note="G->A: Abolishes protease activity."
FT /evidence="ECO:0000269|PubMed:11672525"
FT MUTAGEN 187
FT /note="S->A,G: Abolishes protease activity."
FT /evidence="ECO:0000269|PubMed:11672525,
FT ECO:0000269|PubMed:15047175"
FT MUTAGEN 250
FT /note="H->A: Abolishes protease activity."
FT /evidence="ECO:0000269|PubMed:11672525"
SQ SEQUENCE 303 AA; 34021 MW; 2B6CB8291319C2D9 CRC64;
MAAVHDLEME SMNLNMGREM KEELEEEEKM REDGGGKDRA KSKKVHRIVS KWMLPEKSRG
TYLERANCFP PPVFIISISL AELAVFIYYA VWKPQKQWIT LDTGILESPF IYSPEKREEA
WRFISYMLVH AGVQHILGNL CMQLVLGIPL EMVHKGLRVG LVYLAGVIAG SLASSIFDPL
RYLVGASGGV YALMGGYFMN VLVNFQEMIP AFGIFRLLII ILIIVLDMGF ALYRRFFVPE
DGSPVSFAAH IAGGFAGMSI GYTVFSCFDK ALLKDPRFWI AIAAYLACVL FAVFFNIFLS
PAN
