HRK (harakiri, BCL2 interacting protein (contains only BH3 domain))

Alias_names	harakiri
Alias_symbol (synonym)	DP5
Other alias	HARAKIRI
	BID3
HGNC (Hugo)	HRK
LocusID (NCBI)	8739
Atlas_Id	40865
Location	12q24.22  [Link to chromosome band 12q24]
Location_base_pair	Starts at 116860420 and ends at 116881427 bp from pter ( according to hg19-Feb_2009)  [Mapping HRK.png]
Local_order	According to Ensembl and the NCBI Map Viewer, the genes flanking HRK in the plus strand direction are: RNFT2, which is downstream of HRK and transcribed towards it, and FBXW8, which is upstream of HRK and transcribed divergently.
	Figure 1. Genomic context of the human HRK gene. HRK is located on chromosome 12 between the RNFT2 and FBXW8 genes. Arrows indicate the 5' to 3' orientation of each gene. Adapted from the NCBI Map Viewer.

	Figure 2. HRK gene and promoter structure. A. Structure of the HRK gene. The structure of the human and rat HRK genes is shown. The HRK gene consists of two exons separated by a large intron. The transcriptional start site is indicated as +1 (see panel B for DNA sequence). Exon 1 contains the HRK open reading frame (black box) as well as a small region of the 3' UTR, the remainder of which is in exon 2. Exon 2 is longer in the rat and mouse genes compared to Exon 2 in human HRK. The human HRK transcript is 716 nucleotides long (Inohara et al., 1997) whereas the rat HRK transcript is 5253 nucleotides long due to the larger size of Exon 2 (Imaizumi et al., 1997). B. HRK promoter sequence. Alignment of the promoter sequences for the rat, mouse, human and cow HRK genes. Shaded regions indicate a conserved ATF site, a GC box, an E box and a TATA box. * represent bases conserved in all four species. Overall, 80% of the nucleotides are conserved. The transcriptional start site of the rat HRK gene determined by 5' RACE is indicated as +1, together with the direction of transcription (Towers et al., 2009). The HRK promoter has a similar structure in the four species except that there is a 10 bp deletion between the ATF site and putative GC box in the human gene, compared to the other species. Adapted from Figure 3 in Towers et al. (2009).
Description	The human HRK gene spans 20206 bases, telomere to centromere orientation. Exon 2, which encodes the 3' UTR of the HRK mRNA, is much longer in the mouse and rat genes compared to human HRK (see Figure 2A). In the three species only one major transcript encoding a single protein isoform has been described.
Transcription	In northern blotting experiments with RNA from human tissues, it was reported that the HRK transcript was detected in spleen, lymph nodes, thymus, bone marrow and appendix (Inohara et al., 1997). However, in the rat and mouse the expression of the HRK transcript is much more restricted and HRK is detected in the brain but not the spleen, thymus, bone marrow, liver, lung, testis, heart, intestine or skeletal muscle (Imaizumi et al., 1997; Coultas et al., 2007). Based on studies with the rat HRK gene (Ma et al., 2007; Towers et al., 2009), the 1 kb region upstream of exon 1 contains elements important for the control of HRK transcription (Figure 2B). The HRK promoter is GC-rich but contains a conserved block of 14 A/T nucleotides that might function as a TATA box, a conserved E-box, a conserved GC box and a conserved and functionally-important ATF binding site (5'-TGATGTAA-3') that binds c-Jun and ATF2 and which is important for the activation of HRK transcription by the JNK pathway following survival factor withdrawal in neurons (Ma et al., 2007; Towers et al., 2009) or exposure to pro-inflammatory cytokines in pancreatic beta-cells (Gurzov et al., 2009).
Pseudogene	There are no known pseudogenes for HRK.

	Figure 3. Structure of the human and rat HRK proteins. Amino acid residues in the 91 amino acid human HRK protein are numbered. Residues that are identical in the human and rat HRK proteins are shaded. Gaps are indicated by -. The BH3 domain and transmembrane domain are marked by black lines.
Description	Only one isoform of the HRK protein has been described. HRK is 91 amino acids long in humans and 92 amino acids in mouse and rat (Inohara et al., 1997; Imaizumi et al., 1997; Imaizumi et al., 1999).
Expression	See section on transcription for information about tissue specificity. The endogenous HRK protein has been detected in immunoblotting experiments with a number of cell types, for example: in NGF-deprived rat primary sympathetic neurons in culture (Imaizumi et al., 1997), in the mouse brain following focal cerebral ischemia (middle cerebral artery occlusion; Gao et al., 2005), in the auditory cell line HEI-OC1 exposed to gentimicin (Kalinec et al., 2005) and in the pancreatic beta-cell line INS-1E treated with the pro-inflammatory cytokines IL-1beta and IFNgamma (Gurzov et al., 2009).
Localisation	HRK is a non-nuclear intracellular protein (Inohara et al., 1997). Flag-tagged HRK co-localizes with MitoTracker in transfected COS-7 cells suggesting that HRK predominantly localizes to mitochondria (Sunayama et al., 2004). Studies with a 27 amino acid peptide containing the putative transmembrane domain of HRK indicated that this domain is able to insert into membranes, where it adopts a transmembrane alpha-helical structure (Bernabeu et al., 2007). This suggests that the carboxy terminal region of HRK may insert into the mitochondrial outer membrane.
Function	HRK is a pro-apoptotic BH3-only member of the Bcl-2 protein family. Overexpression of HRK can induce apoptosis in HEK293 cells (Inohara et al., 1997; Imaizumi et al., 1999), rat sympathetic neurons (Imaizumi et al., 1997) and cerebellar granule neurons (Harris and Johnson, 2001). In these cell types HRK/DP5-induced apoptosis is blocked by co-expression of Bcl-2 or Bcl-xL (Inohara et al., 1997; Imaizumi et al., 1997) or by knockout of the endogenous Bax gene (Harris and Johnson, 2001). The HRK protein contains two functional domains: a BH3 domain and a carboxy terminal transmembrane domain (Figure 3). The HRK BH3 domain is related in amino acid sequence to the BH3 domains of other Bcl-2 family proteins and is required for interaction with anti-apoptotic Bcl-2 family proteins, such as Bcl-2 and Bcl-xL, and for cell death induced by overexpression of HRK (Inohara et al., 1997). A detailed study of the binding of BH3-only proteins to anti-apoptotic Bcl-2 family members indicated that HRK binds with high affinity to Bcl-xL, Bcl-w and A1 and with moderate affinity to Bcl-2 and Mcl-1 (Chen et al., 2005). The HRK transmembrane domain is rich in hydrophobic amino acid residues and could mediate the insertion of the HRK carboxy terminus into intracellular membranes, such as the mitrochondrial outer membrane.
Homology	The HRK protein is only related to other Bcl-2 family proteins in the short BH3 domain.

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