GRPEL1

Summary

GRPEL1 (GrpE like 1, mitochondrial, HGNC:19696) is a protein-coding gene on chromosome 4p16.1, encoding GrpE protein homolog 1, mitochondrial (Q9HAV7). Essential component of the PAM complex, a complex required for the translocation of transit peptide-containing proteins from the inner membrane into the mitochondrial matrix in an ATP-dependent manner. It is a common-essential gene (DepMap: required in 98.8% of cancer cell lines).

Enables identical protein binding activity and unfolded protein binding activity. Predicted to be involved in protein import into mitochondrial matrix. Located in mitochondrial matrix and nucleoplasm.

Source: NCBI Gene 80273 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 36 total
• Cancer dependency (DepMap): dependent in 98.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_025196

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19696
Approved symbol	GRPEL1
Name	GrpE like 1, mitochondrial
Location	4p16.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25609, GrpE, hMGE
Ensembl gene	ENSG00000109519
Ensembl biotype	protein_coding
OMIM	606173
Entrez	80273

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000264954, ENST00000504920, ENST00000509696, ENST00000514056, ENST00000706688, ENST00000706689, ENST00000706690, ENST00000869291, ENST00000869292, ENST00000869293, ENST00000915215, ENST00000915216

RefSeq mRNA: 1 — MANE Select: NM_025196 NM_025196

CCDS: CCDS3396

Canonical transcript exons

ENST00000264954 — 4 exons

Exon	Start	End
ENSE00003996598	7062385	7062466
ENSE00003996599	7067971	7068064
ENSE00003996602	7064061	7064223
ENSE00003996603	7058895	7061208

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 96.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.6791 / max 753.4331, expressed in 1817 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51279	46.6791	1817

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left adrenal gland	UBERON:0001234	96.67	gold quality
right adrenal gland	UBERON:0001233	96.54	gold quality
right adrenal gland cortex	UBERON:0035827	96.40	gold quality
left adrenal gland cortex	UBERON:0035825	96.22	gold quality
adrenal gland	UBERON:0002369	96.04	gold quality
secondary oocyte	CL:0000655	95.65	gold quality
adrenal tissue	UBERON:0018303	95.62	gold quality
adrenal cortex	UBERON:0001235	95.50	gold quality
oocyte	CL:0000023	95.29	gold quality
gastrocnemius	UBERON:0001388	94.32	gold quality
muscle of leg	UBERON:0001383	93.98	gold quality
right lobe of liver	UBERON:0001114	93.44	gold quality
heart left ventricle	UBERON:0002084	93.09	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.01	gold quality
cardiac ventricle	UBERON:0002082	92.86	gold quality
islet of Langerhans	UBERON:0000006	92.81	gold quality
monocyte	CL:0000576	92.46	gold quality
mononuclear cell	CL:0000842	92.41	gold quality
nephron tubule	UBERON:0001231	92.33	gold quality
liver	UBERON:0002107	92.29	gold quality
leukocyte	CL:0000738	92.19	gold quality
muscle organ	UBERON:0001630	92.10	gold quality
mucosa of transverse colon	UBERON:0004991	92.10	gold quality
skeletal muscle organ	UBERON:0014892	92.10	gold quality
left testis	UBERON:0004533	91.40	gold quality
cartilage tissue	UBERON:0002418	91.01	gold quality
right testis	UBERON:0004534	90.99	gold quality
adult mammalian kidney	UBERON:0000082	90.98	gold quality
heart	UBERON:0000948	90.86	gold quality
apex of heart	UBERON:0002098	90.80	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-5	no	2.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

73 targeting GRPEL1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 4)

• The low resolution structure of human GrpE presented suggests that GrpE is a symmetric dimer when not bound to DnaK (PMID:12840016)
• Data suggest that two putative NEF (nucleotide exchange factors) orthologs, GRPEL1 and GRPEL2, modulate function of mitochondrial HSP70 (mtHSP70); both GRPEL1 and GRPEL2 associate with mtHSP70 as hetero-oligomeric subcomplex and regulate mtHSP70 transport. (GRPEL = mitochondrial GrpE-like protein; HSP70 = heat-shock protein 70) (PMID:28848044)
• These data demonstrate that LIV-1-GRPEL1 axis dually regulates mitotic exit as well as apoptosis by interacting with PP2A B55alpha and AIF. (PMID:31636012)
• Preferential binding of ADP-bound mitochondrial HSP70 to the nucleotide exchange factor GRPEL1 over GRPEL2. (PMID:39445986)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	grpel1	ENSDARG00000010021
mus_musculus	Grpel1	ENSMUSG00000029198
rattus_norvegicus	Grpel1	ENSRNOG00000006593
drosophila_melanogaster	Roe1	FBGN0014877
caenorhabditis_elegans		WBGENE00007927

Paralogs (1): GRPEL2 (ENSG00000164284)

Protein

Protein identifiers

GrpE protein homolog 1, mitochondrial — Q9HAV7 (reviewed: Q9HAV7)

Alternative names: HMGE, Mt-GrpE#1

All UniProt accessions (3): Q9HAV7, A0A9L9PX72, A0A9L9PY91

UniProt curated annotations — full annotation on UniProt →

Function. Essential component of the PAM complex, a complex required for the translocation of transit peptide-containing proteins from the inner membrane into the mitochondrial matrix in an ATP-dependent manner. Seems to control the nucleotide-dependent binding of mitochondrial HSP70 to substrate proteins.

Subunit / interactions. Probable component of the PAM complex at least composed of a mitochondrial HSP70 protein, GRPEL1 or GRPEL2, TIMM44, TIMM16/PAM16 and TIMM14/DNAJC19. Binds to HSP70, HSC70 and HSJ1B.

Subcellular location. Mitochondrion matrix.

Similarity. Belongs to the GrpE family.

RefSeq proteins (1): NP_079472* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000740	GrpE	Family
IPR009012	GrpE_head	Homologous_superfamily
IPR013805	GrpE_CC	Homologous_superfamily

Pfam: PF01025

UniProt features (10 total): modified residue 6, transit peptide 1, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9BLS	ELECTRON MICROSCOPY	2.96
9BLT	ELECTRON MICROSCOPY	3.38
9BLU	ELECTRON MICROSCOPY	3.38

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HAV7-F1	80.56	0.59

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (6): 94, 94, 100, 120, 215, 215

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-9918481	Dengue Virus-Host Interactions

MSigDB gene sets: 182 (showing top): GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, WEI_MYCN_TARGETS_WITH_E_BOX, BROWNE_HCMV_INFECTION_24HR_UP, GOBP_PROTEIN_MATURATION, GOCC_MITOCHONDRIAL_ENVELOPE, chr4p16, GOBP_PROTEIN_FOLDING, PPAR_DR1_Q2, SCHLOSSER_MYC_TARGETS_AND_SERUM_RESPONSE_UP, DODD_NASOPHARYNGEAL_CARCINOMA_UP, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_PROTEIN_TRANSMEMBRANE_TRANSPORT, DOUGLAS_BMI1_TARGETS_UP

GO Biological Process (3): protein folding (GO:0006457), intracellular protein transport (GO:0006886), protein import into mitochondrial matrix (GO:0030150)

GO Molecular Function (6): adenyl-nucleotide exchange factor activity (GO:0000774), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), obsolete unfolded protein binding (GO:0051082), protein-folding chaperone binding (GO:0051087), protein binding (GO:0005515)

GO Cellular Component (6): PAM complex, Tim23 associated import motor (GO:0001405), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), TIM23 mitochondrial import inner membrane translocase complex (GO:0005744), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein localization	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	2
inner mitochondrial membrane protein complex	2
cellular process	1
protein maturation	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
protein transmembrane import into intracellular organelle	1
protein localization to mitochondrion	1
import into the mitochondrion	1
mitochondrial protein import pathway	1
ATP binding	1
ADP binding	1
ATPase regulator activity	1
identical protein binding	1
protein dimerization activity	1
binding	1
TIM23 mitochondrial import inner membrane translocase complex	1
mitochondrial matrix	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

3036 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRPEL1	TIMM44	O43615	971
GRPEL1	HSPE1	P61604	967
GRPEL1	CLPB	Q9H078	955
GRPEL1	HSPA9	P30036	942
GRPEL1	HSPD1	P10809	916
GRPEL1	HSPA4	P34932	904
GRPEL1	DNAJB1	P25685	892
GRPEL1	TIMM17A	Q99595	875
GRPEL1	CLPX	O76031	846
GRPEL1	TIMM10	P62072	826
GRPEL1	CLPP	Q16740	810
GRPEL1	PAM16	Q9Y3D7	769
GRPEL1	HSPBP1	Q9NZL4	755
GRPEL1	DNAJB6	O75190	736
GRPEL1	BAG1	Q99933	721

IntAct

141 interactions, top by confidence:

A	B	Type	Score
IFIT1	IFIT3	psi-mi:“MI:0914”(association)	0.920
PSMD10	PSMD11	psi-mi:“MI:0914”(association)	0.800
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
GRPEL1	HSPA9	psi-mi:“MI:0915”(physical association)	0.670
GRPEL1	HSPA9	psi-mi:“MI:0914”(association)	0.670
rep	AP2A2	psi-mi:“MI:0914”(association)	0.660
SH3KBP1	USP27X	psi-mi:“MI:0914”(association)	0.640
GRPEL1	GRPEL1	psi-mi:“MI:0915”(physical association)	0.630
POLR1C	GRPEL1	psi-mi:“MI:0915”(physical association)	0.600
AURKB	SEC16A	psi-mi:“MI:2364”(proximity)	0.570
GALT	GRPEL1	psi-mi:“MI:0915”(physical association)	0.560
GRPEL1	SPG21	psi-mi:“MI:0915”(physical association)	0.560
CCDC57	GRPEL1	psi-mi:“MI:0915”(physical association)	0.560
SPATA24	GGPS1	psi-mi:“MI:0914”(association)	0.530
DENND2D	HSPA8	psi-mi:“MI:0914”(association)	0.530
MCEE	CLUH	psi-mi:“MI:0914”(association)	0.530

BioGRID (282): GRPEL1 (Affinity Capture-RNA), GRPEL1 (Affinity Capture-RNA), CCAR1 (Affinity Capture-MS), PALLD (Affinity Capture-MS), GRPEL2 (Affinity Capture-MS), GRPEL1 (Affinity Capture-MS), AHNAK (Co-fractionation), DNAJA4 (Co-fractionation), DNAJB1 (Co-fractionation), DNAJB4 (Co-fractionation), DNAJC3 (Co-fractionation), DUT (Co-fractionation), GRPEL1 (Co-fractionation), GRPEL1 (Co-fractionation), GRPEL1 (Co-fractionation)

ESM2 similar proteins: A0Q7F1, A4IX27, A6ZP58, A7NCM8, A7ZEB6, A9NFN7, B0SHT2, B0SRF2, B0TYF1, B2IDD9, B2SGV9, B3LJN9, B3QTT2, B5VS96, C4XYS2, C5DEW2, C5DXN2, C7GWG7, C8ZGX0, O43047, O74479, P09457, P38523, P48204, P48604, P97576, Q049W5, Q0BLK5, Q12032, Q14GW8, Q18421, Q2A329, Q3SZC1, Q54QF9, Q5NFG6, Q5NRL4, Q5RA81, Q6BTP9, Q6C9B1, Q6CRQ1

Diamond homologs: A0KMI7, A0KZB0, A0Q7F1, A1RLV4, A1S8D5, A1UUC9, A3D2B1, A4IX27, A4SQ26, A4Y4W9, A4YJR1, A5F369, A5V5Q2, A5VNA6, A6U5E2, A6WL03, A6WVA7, A7HZ43, A7NCM8, A8FYL1, A8H6X2, A9GHU4, A9ILE9, A9KTL2, A9M7B6, B0CJ30, B0T367, B0TQ37, B0TYF1, B1KQY9, B2IDD9, B2SGV9, B3PZA4, B3Q970, B5ZMX0, B6JCI1, B7VJW7, B8CS27, B8EAU9, B8ET77

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GRPEL1	“down-regulates activity”	HSPA8	binding
GRPEL1	“form complex”	“TIM23 complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

36 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	28
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

643 predictions. Top by Δscore:

Variant	Effect	Δscore
4:7061206:TGC:T	acceptor_gain	1.0000
4:7061207:GCC:G	acceptor_loss	1.0000
4:7061208:CCTG:C	acceptor_loss	1.0000
4:7061209:C:CC	acceptor_gain	1.0000
4:7062382:TACC:T	donor_loss	1.0000
4:7062383:A:AC	donor_gain	1.0000
4:7062384:C:CC	donor_gain	1.0000
4:7062384:CCGTA:C	donor_loss	1.0000
4:7062399:T:TA	donor_gain	1.0000
4:7062462:TTTTC:T	acceptor_gain	1.0000
4:7062463:TTTC:T	acceptor_gain	1.0000
4:7062464:TTC:T	acceptor_gain	1.0000
4:7062465:TC:T	acceptor_gain	1.0000
4:7062466:CC:C	acceptor_gain	1.0000
4:7062466:CCT:C	acceptor_loss	1.0000
4:7062467:C:CA	acceptor_loss	1.0000
4:7062467:C:CC	acceptor_gain	1.0000
4:7062468:T:A	acceptor_loss	1.0000
4:7064050:ACAGT:A	donor_gain	1.0000
4:7064051:CAGTC:C	donor_gain	1.0000
4:7064055:CCTCA:C	donor_loss	1.0000
4:7064056:CTCA:C	donor_loss	1.0000
4:7064058:CACC:C	donor_loss	1.0000
4:7064059:A:AC	donor_gain	1.0000
4:7064060:C:CC	donor_gain	1.0000
4:7064060:CCA:C	donor_gain	1.0000
4:7064219:ATGGC:A	acceptor_gain	1.0000
4:7064220:TGGC:T	acceptor_gain	1.0000
4:7064221:GGC:G	acceptor_gain	1.0000
4:7064222:GC:G	acceptor_gain	1.0000

AlphaMissense

1410 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:7062451:C:G	A81P	0.999
4:7061155:C:G	A121P	0.998
4:7060896:C:G	R207T	0.997
4:7060923:C:T	G198E	0.997
4:7061006:G:C	F170L	0.997
4:7061006:G:T	F170L	0.997
4:7061008:A:G	F170L	0.997
4:7061085:A:G	L144P	0.997
4:7061192:G:C	C108W	0.997
4:7062397:C:G	A99P	0.997
4:7062426:C:G	R89P	0.997
4:7060895:T:A	R207S	0.996
4:7060895:T:G	R207S	0.996
4:7060905:C:G	R204P	0.996
4:7060906:G:T	R204S	0.996
4:7061037:A:G	L160S	0.996
4:7061097:A:G	L140P	0.996
4:7061163:A:G	L118P	0.996
4:7061193:C:T	C108Y	0.996
4:7061194:A:G	C108R	0.996
4:7062453:C:G	R80P	0.996
4:7060914:A:G	L201P	0.995
4:7060921:A:C	Y199D	0.995
4:7060924:C:A	G198W	0.995
4:7060924:C:G	G198R	0.995
4:7060924:C:T	G198R	0.995
4:7061089:C:G	G143R	0.995
4:7061089:C:T	G143R	0.995
4:7061142:A:T	V125D	0.995
4:7060890:G:T	A209D	0.994

dbSNP variants (sampled 300 via entrez): RS1000228503 (4:7061757 C>T), RS1000535252 (4:7063266 T>C), RS1000656791 (4:7067355 G>A), RS1000686735 (4:7062287 C>A,T), RS1000966325 (4:7062998 G>A), RS1001431082 (4:7068166 A>G), RS1001504715 (4:7067842 A>G), RS1001712582 (4:7068322 A>G), RS1001807854 (4:7058450 G>C), RS1002079813 (4:7068415 C>G,T), RS1002287919 (4:7064530 T>C), RS1002759661 (4:7069044 C>G,T), RS1002860854 (4:7059501 G>A,T), RS1003034200 (4:7063582 C>A,G,T), RS1003137431 (4:7068699 T>C)

Disease associations

OMIM: gene MIM:606173 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002382_591	Eosinophil percentage of white cells	4.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

61 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects expression, increases expression, affects cotreatment, increases abundance	3
Air Pollutants	affects expression, increases abundance, decreases expression	2
Cisplatin	decreases expression, increases expression	2
Ethyl Methanesulfonate	decreases expression	2
Methyl Methanesulfonate	decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	increases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance, affects cotreatment	2
dicrotophos	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	increases expression	1
sodium arsenate	decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases abundance, increases expression, affects cotreatment	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
isobutyl alcohol	affects cotreatment, increases abundance, increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
LDN 193189	decreases expression, affects cotreatment	1
PCI 5002	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Acetaminophen	decreases expression	1
Adenine	decreases expression	1
Atrazine	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.