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2  structures 15  species 0  interactions 15  sequences 1  architecture

Family: Harakiri (PF15196)

Summary: Activator of apoptosis harakiri

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This is the Wikipedia entry entitled "HRK (gene)". More...

HRK (gene) Edit Wikipedia article

Harakiri, BCL2 interacting protein
Available structures
PDB Ortholog search: PDBe, RCSB
External IDs OMIM603447 MGI1201608 HomoloGene136405 GeneCards: HRK Gene
RNA expression pattern
PBB GE HRK 206865 at tn.png
PBB GE HRK 206864 s at tn.png
More reference expression data
Species Human Mouse
Entrez 8739 12123
Ensembl ENSG00000135116 ENSMUSG00000046607
UniProt O00198 P62816
RefSeq (mRNA) NM_003806 NM_007545
RefSeq (protein) NP_003797 NP_031571
Location (UCSC) Chr 12:
117.29 – 117.32 Mb
Chr 5:
118.17 – 118.19 Mb
PubMed search [1] [2]

Activator of apoptosis harakiri is a protein that in humans is encoded by the HRK gene.[1][2]


Activator of apoptosis Hrk regulates apoptosis through interaction with death-repressor proteins Bcl-2 and Bcl-X(L). The HRK protein lacks significant homology to other BCL2 family members except for an 8-amino acid region that was similar to the BCL2 homology domain-3 (BH3) motif of BIK. HRK interacts with BCL2 and BCLXL via the BH3 domain, but not with the death-promoting BCL2-related proteins BAX, BAK, or BCLXS. HRK localizes to membranes of intracellular organelles in a pattern similar to that previously reported for BCL2 and BCLXL.[2]


HRK (gene) has been shown to interact with:


  1. ^ a b c Inohara N, Ding L, Chen S, Núñez G (May 1997). "harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L)". EMBO J 16 (7): 1686–94. doi:10.1093/emboj/16.7.1686. PMC 1169772. PMID 9130713. 
  2. ^ a b "Entrez Gene: HRK harakiri, BCL2 interacting protein (contains only BH3 domain)". 
  3. ^ Whitfield J, Harada K, Bardelle C, Staddon JM (Nov 2003). "High-throughput methods to detect dimerization of Bcl-2 family proteins". Anal. Biochem. 322 (2): 170–8. doi:10.1016/j.ab.2003.07.014. PMID 14596824. 
  4. ^ Imaizumi K, Morihara T, Mori Y, Katayama T, Tsuda M, Furuyama T, Wanaka A, Takeda M, Tohyama M (Mar 1999). "The cell death-promoting gene DP5, which interacts with the BCL2 family, is induced during neuronal apoptosis following exposure to amyloid beta protein". J. Biol. Chem. 274 (12): 7975–81. doi:10.1074/jbc.274.12.7975. PMID 10075695. 
  5. ^ Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (Feb 2005). "Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function". Mol. Cell 17 (3): 393–403. doi:10.1016/j.molcel.2004.12.030. PMID 15694340. 

Further reading

  • Imaizumi K, Morihara T, Mori Y, Katayama T, Tsuda M, Furuyama T, Wanaka A, Takeda M, Tohyama M (1999). "The cell death-promoting gene DP5, which interacts with the BCL2 family, is induced during neuronal apoptosis following exposure to amyloid beta protein.". J. Biol. Chem. 274 (12): 7975–81. doi:10.1074/jbc.274.12.7975. PMID 10075695. 
  • Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination.". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863. 
  • Sanz C, Mellstrom B, Link WA, Naranjo JR, Fernandez-Luna JL (2001). "Interleukin 3-dependent activation of DREAM is involved in transcriptional silencing of the apoptotic Hrk gene in hematopoietic progenitor cells.". EMBO J. 20 (9): 2286–92. doi:10.1093/emboj/20.9.2286. PMC 125442. PMID 11331593. 
  • Bae J, Hsu SY, Leo CP, Zell K, Hsueh AJ (2001). "Underphosphorylated BAD interacts with diverse antiapoptotic Bcl-2 family proteins to regulate apoptosis.". Apoptosis 6 (5): 319–30. doi:10.1023/A:1011319901057. PMID 11483855. 
  • Wakabayashi T, Kosaka J, Hommura S (2002). "Up-regulation of Hrk, a regulator of cell death, in retinal ganglion cells of axotomized rat retina.". Neurosci. Lett. 318 (2): 77–80. doi:10.1016/S0304-3940(01)02487-9. PMID 11796190. 
  • Sanz C, Horita M, Fernandez-Luna JL (2004). "Fas signaling and blockade of Bcr-Abl kinase induce apoptotic Hrk protein via DREAM inhibition in human leukemia cells.". Haematologica 87 (9): 903–7. PMID 12217801. 
  • Jurisicova A, Antenos M, Varmuza S, Tilly JL, Casper RF (2003). "Expression of apoptosis-related genes during human preimplantation embryo development: potential roles for the Harakiri gene product and Caspase-3 in blastomere fragmentation.". Mol. Hum. Reprod. 9 (3): 133–41. doi:10.1093/molehr/gag016. PMID 12606589. 
  • Whitfield J, Harada K, Bardelle C, Staddon JM (2004). "High-throughput methods to detect dimerization of Bcl-2 family proteins.". Anal. Biochem. 322 (2): 170–8. doi:10.1016/j.ab.2003.07.014. PMID 14596824. 
  • Obata T, Toyota M, Satoh A, Sasaki Y, Ogi K, Akino K, Suzuki H, Murai M, Kikuchi T, Mita H, Itoh F, Issa JP, Tokino T, Imai K (2004). "Identification of HRK as a target of epigenetic inactivation in colorectal and gastric cancer.". Clin. Cancer Res. 9 (17): 6410–8. PMID 14695142. 
  • Sunayama J, Ando Y, Itoh N, Tomiyama A, Sakurada K, Sugiyama A, Kang D, Tashiro F, Gotoh Y, Kuchino Y, Kitanaka C (2005). "Physical and functional interaction between BH3-only protein Hrk and mitochondrial pore-forming protein p32.". Cell Death Differ. 11 (7): 771–81. doi:10.1038/sj.cdd.4401418. PMID 15031724. 
  • Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (2005). "Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function.". Mol. Cell 17 (3): 393–403. doi:10.1016/j.molcel.2004.12.030. PMID 15694340. 
  • Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, Newmeyer DD (2005). "BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly.". Mol. Cell 17 (4): 525–35. doi:10.1016/j.molcel.2005.02.003. PMID 15721256. 
  • Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, Letai A (2006). "Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members.". Cancer Cell 9 (5): 351–65. doi:10.1016/j.ccr.2006.03.027. PMID 16697956. 

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Activator of apoptosis harakiri Provide feedback

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External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR017249

Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans [PUBMED:11341280]. In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.

The protein harakiri (Hrk, also called death protein 5, DP5) is a pro-apoptotic Bcl-2 homology domain 3-only (BH3-only) member protein, which belongs to the Bcl-2 family. Hrk is associated to the mitochondrial outer membrane via a putative trans-membrane domain at the C-terminal, which adopts a predominantly alpha-helical structure. This domain is able to insert itself into membranes where it perturbs the physical properties of the membrane considerably [PUBMED:17434443].

It can be activated by a diverse array of developmental cues or experimentally applied stress stimuli. Hrk contributes to apoptosis signalling elicited by trophic factor withdrawal in certain neuronal cells but is not critical for apoptosis of haematopoietic cells [PUBMED:17535852]. DP5 is important in neuronal cell death that can be induced by axotomy and neuronal growth factor (NGF) deprivation. It acts by regulating the mitochondrial function and caspase-3 activation [PUBMED:15084651].

Apoptosis regulation is a main cause of epithelial dysfunction in patients with ulcerative colitis. Six genes were found to be highly expressed in epithelial cells from people with and without ulcerative colitis, one of which is Hrk [PUBMED:16907856]. Hrk is also up-regulated in a JNK-dependent manner during apoptosis induced by potassium deprivation in cerebellar granule neurons [PUBMED:17428807].

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Seed source: Jackhmmer:O00198
Previous IDs: none
Type: Family
Author: Eberhardt RY, Coggill P, Hetherington K
Number in seed: 2
Number in full: 15
Average length of the domain: 88.40 aa
Average identity of full alignment: 89 %
Average coverage of the sequence by the domain: 100.00 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 27.0
Trusted cut-off 60.9 60.8
Noise cut-off 26.5 26.5
Model length: 92
Family (HMM) version: 2
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Harakiri domain has been found. There are 2 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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