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Protein

Rhomboid-related protein 4

Gene

RHBDD1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Intramembrane-cleaving serine protease that cleaves single transmembrane or multi-pass membrane proteins in the hydrophobic plane of the membrane, luminal loops and juxtamembrane regions. Involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors. Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded membrane proteins. Required for the degradation process of some specific misfolded endoplasmic reticulum (ER) luminal proteins. Participates in the transfer of misfolded proteins from the ER to the cytosol, where they are destroyed by the proteasome in a ubiquitin-dependent manner. Functions in BIK, MPZ, PKD1, PTCRA, RHO, STEAP3 and TRAC processing. Involved in the regulation of exosomal secretion; inhibits the TSAP6-mediated secretion pathway. Involved in the regulation of apoptosis; modulates BIK-mediated apoptotic activity. Also plays a role in the regulation of spermatogenesis; inhibits apoptotic activity in spermatogonia.2 Publications

Catalytic activityi

Cleaves type-1 transmembrane domains using a catalytic dyad composed of serine and histidine that are contributed by different transmembrane domains.

Enzyme regulationi

Inhibited by aprotinin.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei144 – 1441NucleophileBy similarity
Active sitei195 – 1951By similarity

GO - Molecular functioni

  • endopeptidase activity Source: UniProtKB
  • serine-type endopeptidase activity Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Serine protease

Keywords - Biological processi

Apoptosis, Differentiation, Spermatogenesis

Protein family/group databases

MEROPSiS54.008.
TCDBi9.B.104.4.1. the rhomboid protease (rhomboid) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Rhomboid-related protein 4 (EC:3.4.21.105)
Short name:
RRP4
Alternative name(s):
Rhomboid domain-containing protein 1
Rhomboid-like protein 4
Gene namesi
Name:RHBDD1
Synonyms:RHBDL4
ORF Names:HSD-50, HSD50
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

HGNCiHGNC:23081. RHBDD1.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 2121CytoplasmicSequence analysisAdd
BLAST
Transmembranei22 – 4221HelicalSequence analysisAdd
BLAST
Topological domaini43 – 10664ExtracellularSequence analysisAdd
BLAST
Transmembranei107 – 12721HelicalSequence analysisAdd
BLAST
Topological domaini128 – 14518CytoplasmicSequence analysisAdd
BLAST
Transmembranei146 – 16621HelicalSequence analysisAdd
BLAST
Topological domaini167 – 18014ExtracellularSequence analysisAdd
BLAST
Transmembranei181 – 20121HelicalSequence analysisAdd
BLAST
Topological domaini202 – 315114CytoplasmicSequence analysisAdd
BLAST

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane, Mitochondrion

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi142 – 1421G → A: Enzyme inactivation. Reduces the cleavage of BIK. 1 Publication
Mutagenesisi144 – 1441S → A: Enzyme inactivation. Reduces the cleavage of BIK and TSAP6. Increases TSAP6-mediated exosome secretion. 2 Publications

Organism-specific databases

PharmGKBiPA143485593.

Polymorphism and mutation databases

BioMutaiRHBDD1.
DMDMi74723955.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 315315Rhomboid-related protein 4PRO_0000254189Add
BLAST

Proteomic databases

EPDiQ8TEB9.
MaxQBiQ8TEB9.
PaxDbiQ8TEB9.
PRIDEiQ8TEB9.

PTM databases

iPTMnetiQ8TEB9.
PhosphoSiteiQ8TEB9.

Expressioni

Tissue specificityi

Expressed strongly in testis.

Inductioni

Up-regulated by endoplasmic reticulum stress agents that induce the unfolded protein response (UPR).1 Publication

Gene expression databases

BgeeiQ8TEB9.
CleanExiHS_RHBDD1.
ExpressionAtlasiQ8TEB9. baseline and differential.
GenevisibleiQ8TEB9. HS.

Organism-specific databases

HPAiHPA013972.

Interactioni

Subunit structurei

Interacts (via C-terminal domain) with VCP. Interacts with ubiquitin and ubiquitinated proteins (By similarity). Interacts with BIK and STEAP3.By similarity2 Publications

Protein-protein interaction databases

BioGridi123968. 11 interactions.
IntActiQ8TEB9. 4 interactions.
STRINGi9606.ENSP00000344779.

Structurei

3D structure databases

ProteinModelPortaliQ8TEB9.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni269 – 28416Ubiquitin-binding domain (UBD)By similarityAdd
BLAST
Regioni301 – 31515VCP/p97-interacting motif (VIM)By similarityAdd
BLAST

Sequence similaritiesi

Belongs to the peptidase S54 family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2632. Eukaryota.
ENOG41100KJ. LUCA.
GeneTreeiENSGT00390000010744.
HOVERGENiHBG054446.
InParanoidiQ8TEB9.
KOiK09651.
OMAiGQQYYFN.
PhylomeDBiQ8TEB9.
TreeFamiTF328476.

Family and domain databases

Gene3Di1.20.1540.10. 1 hit.
InterProiIPR022764. Peptidase_S54_rhomboid_dom.
[Graphical view]
PfamiPF01694. Rhomboid. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8TEB9-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MQRRSRGINT GLILLLSQIF HVGINNIPPV TLATLALNIW FFLNPQKPLY
60 70 80 90 100
SSCLSVEKCY QQKDWQRLLL SPLHHADDWH LYFNMASMLW KGINLERRLG
110 120 130 140 150
SRWFAYVITA FSVLTGVVYL LLQFAVAEFM DEPDFKRSCA VGFSGVLFAL
160 170 180 190 200
KVLNNHYCPG GFVNILGFPV PNRFACWVEL VAIHLFSPGT SFAGHLAGIL
210 220 230 240 250
VGLMYTQGPL KKIMEACAGG FSSSVGYPGR QYYFNSSGSS GYQDYYPHGR
260 270 280 290 300
PDHYEEAPRN YDTYTAGLSE EEQLERALQA SLWDRGNTRN SPPPYGFHLS
310
PEEMRRQRLH RFDSQ
Length:315
Mass (Da):35,823
Last modified:June 1, 2002 - v1
Checksum:iAF81BA8D907BDC63
GO
Isoform 2 (identifier: Q8TEB9-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-209: Missing.
     210-218: LKKIMEACA → MPVFLFKPK

Note: No experimental confirmation available.
Show »
Length:106
Mass (Da):12,346
Checksum:iD757B01FCFCA3B4A
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti263 – 2631T → M in AAI01263 (PubMed:15489334).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti110 – 1101A → T.
Corresponds to variant rs35731955 [ dbSNP | Ensembl ].
VAR_034454

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 209209Missing in isoform 2. 1 PublicationVSP_021203Add
BLAST
Alternative sequencei210 – 2189LKKIMEACA → MPVFLFKPK in isoform 2. 1 PublicationVSP_021204

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY640233 mRNA. Translation: AAU14246.1.
AK074258 mRNA. Translation: BAB85031.1.
AC010735 Genomic DNA. No translation available.
AC073149 Genomic DNA. Translation: AAY24060.1.
BC027900 mRNA. Translation: AAH27900.1.
BC062636 mRNA. Translation: AAH62636.1.
BC089404 mRNA. Translation: AAH89404.1.
BC101262 mRNA. Translation: AAI01263.1.
BC101263 mRNA. Translation: AAI01264.1.
BC101264 mRNA. Translation: AAI01265.1.
BC101265 mRNA. Translation: AAI01266.1.
BC111056 mRNA. Translation: AAI11057.1.
AL512717 mRNA. Translation: CAC21658.2.
CCDSiCCDS2464.1. [Q8TEB9-1]
RefSeqiNP_001161080.1. NM_001167608.1. [Q8TEB9-1]
NP_115652.2. NM_032276.3. [Q8TEB9-1]
UniGeneiHs.471514.

Genome annotation databases

EnsembliENST00000341329; ENSP00000344779; ENSG00000144468. [Q8TEB9-1]
ENST00000392062; ENSP00000375914; ENSG00000144468. [Q8TEB9-1]
GeneIDi84236.
KEGGihsa:84236.
UCSCiuc002voi.4. human. [Q8TEB9-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY640233 mRNA. Translation: AAU14246.1.
AK074258 mRNA. Translation: BAB85031.1.
AC010735 Genomic DNA. No translation available.
AC073149 Genomic DNA. Translation: AAY24060.1.
BC027900 mRNA. Translation: AAH27900.1.
BC062636 mRNA. Translation: AAH62636.1.
BC089404 mRNA. Translation: AAH89404.1.
BC101262 mRNA. Translation: AAI01263.1.
BC101263 mRNA. Translation: AAI01264.1.
BC101264 mRNA. Translation: AAI01265.1.
BC101265 mRNA. Translation: AAI01266.1.
BC111056 mRNA. Translation: AAI11057.1.
AL512717 mRNA. Translation: CAC21658.2.
CCDSiCCDS2464.1. [Q8TEB9-1]
RefSeqiNP_001161080.1. NM_001167608.1. [Q8TEB9-1]
NP_115652.2. NM_032276.3. [Q8TEB9-1]
UniGeneiHs.471514.

3D structure databases

ProteinModelPortaliQ8TEB9.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi123968. 11 interactions.
IntActiQ8TEB9. 4 interactions.
STRINGi9606.ENSP00000344779.

Protein family/group databases

MEROPSiS54.008.
TCDBi9.B.104.4.1. the rhomboid protease (rhomboid) family.

PTM databases

iPTMnetiQ8TEB9.
PhosphoSiteiQ8TEB9.

Polymorphism and mutation databases

BioMutaiRHBDD1.
DMDMi74723955.

Proteomic databases

EPDiQ8TEB9.
MaxQBiQ8TEB9.
PaxDbiQ8TEB9.
PRIDEiQ8TEB9.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000341329; ENSP00000344779; ENSG00000144468. [Q8TEB9-1]
ENST00000392062; ENSP00000375914; ENSG00000144468. [Q8TEB9-1]
GeneIDi84236.
KEGGihsa:84236.
UCSCiuc002voi.4. human. [Q8TEB9-1]

Organism-specific databases

CTDi84236.
GeneCardsiRHBDD1.
HGNCiHGNC:23081. RHBDD1.
HPAiHPA013972.
neXtProtiNX_Q8TEB9.
PharmGKBiPA143485593.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2632. Eukaryota.
ENOG41100KJ. LUCA.
GeneTreeiENSGT00390000010744.
HOVERGENiHBG054446.
InParanoidiQ8TEB9.
KOiK09651.
OMAiGQQYYFN.
PhylomeDBiQ8TEB9.
TreeFamiTF328476.

Miscellaneous databases

ChiTaRSiRHBDD1. human.
GenomeRNAii84236.
NextBioi73704.
PROiQ8TEB9.

Gene expression databases

BgeeiQ8TEB9.
CleanExiHS_RHBDD1.
ExpressionAtlasiQ8TEB9. baseline and differential.
GenevisibleiQ8TEB9. HS.

Family and domain databases

Gene3Di1.20.1540.10. 1 hit.
InterProiIPR022764. Peptidase_S54_rhomboid_dom.
[Graphical view]
PfamiPF01694. Rhomboid. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "A new spermatogenesis-related gene."
    Wang Y., Miao S.Y., Zhang X.D., Qiao Y., Liang G., Wang L.F.
    Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Testis.
  2. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
    Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
    , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
    Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
  3. "Generation and annotation of the DNA sequences of human chromosomes 2 and 4."
    Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H.
    , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K.
    Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  4. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
    Tissue: Eye, Lymph and Pancreas.
  5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 280-315.
    Tissue: Brain.
  6. "A novel member of the Rhomboid family, RHBDD1, regulates BIK-mediated apoptosis."
    Wang Y., Guan X., Fok K.L., Li S., Zhang X., Miao S., Zong S., Koide S.S., Chan H.C., Wang L.
    Cell. Mol. Life Sci. 65:3822-3829(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CLEAVAGE OF BIK, ENZYME REGULATION, SUBCELLULAR LOCATION, INTERACTION WITH BIK, MUTAGENESIS OF GLY-142 AND SER-144.
  7. "Exosome-related multi-pass transmembrane protein TSAP6 is a target of rhomboid protease RHBDD1-induced proteolysis."
    Wan C., Fu J., Wang Y., Miao S., Song W., Wang L.
    PLoS ONE 7:E37452-E37452(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CLEAVAGE OF STEAP3, INTERACTION WITH STEAP3, MUTAGENESIS OF SER-144.
  8. "Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of membrane proteins."
    Fleig L., Bergbold N., Sahasrabudhe P., Geiger B., Kaltak L., Lemberg M.K.
    Mol. Cell 47:558-569(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION, SUBCELLULAR LOCATION.

Entry informationi

Entry nameiRHBL4_HUMAN
AccessioniPrimary (citable) accession number: Q8TEB9
Secondary accession number(s): Q495B9
, Q53S43, Q5EBM8, Q6P5V8, Q8IV60, Q9H057
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 31, 2006
Last sequence update: June 1, 2002
Last modified: March 16, 2016
This is version 95 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Miscellaneous

According to PubMed:22795130; it is not localized in the mitochondrion.

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. Peptidase families
    Classification of peptidase families and list of entries
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.