GRPEL2

Summary

GRPEL2 (GrpE like 2, mitochondrial, HGNC:21060) is a protein-coding gene on chromosome 5q32, encoding GrpE protein homolog 2, mitochondrial (Q8TAA5). 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.

Predicted to enable adenyl-nucleotide exchange factor activity and unfolded protein binding activity. Predicted to be involved in protein import into mitochondrial matrix. Located in mitochondrion.

Source: NCBI Gene 134266 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 37 total
• MANE Select transcript: NM_152407

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21060
Approved symbol	GRPEL2
Name	GrpE like 2, mitochondrial
Location	5q32
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp451C205, Mt-GrpE#2, FLJ23713
Ensembl gene	ENSG00000164284
Ensembl biotype	protein_coding
OMIM	618545
Entrez	134266

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000329271, ENST00000416916, ENST00000507562, ENST00000513661, ENST00000913747

RefSeq mRNA: 1 — MANE Select: NM_152407 NM_152407

CCDS: CCDS4295

Canonical transcript exons

ENST00000329271 — 4 exons

Exon	Start	End
ENSE00003502866	149348272	149348425
ENSE00003576362	149349654	149349735
ENSE00003662005	149350918	149354583
ENSE00003842982	149345499	149345616

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 98.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.0356 / max 195.8147, expressed in 1802 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59358	23.8140	1801
59357	0.2216	88

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.26	gold quality
buccal mucosa cell	CL:0002336	94.89	gold quality
oocyte	CL:0000023	93.64	gold quality
secondary oocyte	CL:0000655	92.14	gold quality
esophagus squamous epithelium	UBERON:0006920	91.29	gold quality
oviduct epithelium	UBERON:0004804	90.22	gold quality
pharyngeal mucosa	UBERON:0000355	89.00	gold quality
esophagus mucosa	UBERON:0002469	88.63	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.42	gold quality
oral cavity	UBERON:0000167	87.76	gold quality
epithelial cell of pancreas	CL:0000083	86.91	silver quality
medial globus pallidus	UBERON:0002477	86.16	gold quality
gingiva	UBERON:0001828	85.47	gold quality
tibialis anterior	UBERON:0001385	85.46	silver quality
kidney epithelium	UBERON:0004819	85.39	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.26	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	84.80	gold quality
deltoid	UBERON:0001476	84.47	silver quality
epithelium of mammary gland	UBERON:0003244	84.45	gold quality
mammary duct	UBERON:0001765	84.43	gold quality
pancreatic ductal cell	CL:0002079	84.36	silver quality
upper arm skin	UBERON:0004263	84.35	silver quality
cortical plate	UBERON:0005343	84.28	gold quality
cerebellar vermis	UBERON:0004720	84.12	gold quality
ventricular zone	UBERON:0003053	83.93	gold quality
endothelial cell	CL:0000115	83.73	silver quality
globus pallidus	UBERON:0001875	83.70	gold quality
ganglionic eminence	UBERON:0004023	83.52	gold quality
lower lobe of lung	UBERON:0008949	83.17	gold quality
mammalian vulva	UBERON:0000997	83.09	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.02

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

173 targeting GRPEL2, 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-4533	100.00	69.48	2758
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-186-5P	99.99	70.83	3707
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AA	99.96	70.64	3753

Literature-anchored findings (GeneRIF, showing 4)

• 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)
• The dimerization of GRPEL2 may activate the folding machinery responsible for protein import into mitochondrial matrix or enhance the chaperone activity of mitochondrial HSP70, thus protecting mitochondrial proteostasis in oxidative stress. (PMID:30098457)
• GRPEL2 Knockdown Exerts Redox Regulation in Glioblastoma. (PMID:34884508)
• 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	grpel2	ENSDARG00000069421
mus_musculus	Grpel2	ENSMUSG00000024580
rattus_norvegicus	Grpel2	ENSRNOG00000064275
drosophila_melanogaster	Roe1	FBGN0014877
caenorhabditis_elegans		WBGENE00007927

Paralogs (1): GRPEL1 (ENSG00000109519)

Protein

Protein identifiers

GrpE protein homolog 2, mitochondrial — Q8TAA5 (reviewed: Q8TAA5)

Alternative names: Mt-GrpE#2

All UniProt accessions (2): Q8TAA5, D6RGI6

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. Stimulates ATPase activity of mt-HSP70. May also serve to modulate the interconversion of oligomeric (inactive) and monomeric (active) forms of mt-HSP70.

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.

Subcellular location. Mitochondrion matrix.

Similarity. Belongs to the GrpE family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TAA5-1	1	yes
Q8TAA5-2	2

RefSeq proteins (1): NP_689620* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF01025

UniProt features (5 total): splice variant 2, transit peptide 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TAA5-F1	78.71	0.54

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 (1): 142

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import

MSigDB gene sets: 173 (showing top): RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, AAGCCAT_MIR135A_MIR135B, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_PROTEIN_MATURATION, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_PROTEIN_FOLDING, CHO_NR4A1_TARGETS, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, FISCHER_DREAM_TARGETS, SENESE_HDAC1_TARGETS_UP, GOBP_PROTEIN_TRANSMEMBRANE_TRANSPORT, WONG_MITOCHONDRIA_GENE_MODULE, GOBP_PROTEIN_LOCALIZATION_TO_MITOCHONDRION, ACEVEDO_LIVER_CANCER_UP

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

GO Molecular Function (5): adenyl-nucleotide exchange factor activity (GO:0000774), protein homodimerization activity (GO:0042803), obsolete unfolded protein binding (GO:0051082), protein-folding chaperone binding (GO:0051087), protein binding (GO:0005515)

GO Cellular Component (5): PAM complex, Tim23 associated import motor (GO:0001405), 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-1 pathways:

Category	Pathways
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
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
protein binding	1
binding	1
TIM23 mitochondrial import inner membrane translocase complex	1
mitochondrial matrix	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

2468 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRPEL2	DNAJA3	Q96EY1	707
GRPEL2	HSPA9	P30036	605
GRPEL2	AFAP1L1	Q8TED9	575
GRPEL2	HSPA12A	O43301	572
GRPEL2	HSPE1	P61604	551
GRPEL2	CLPX	O76031	523
GRPEL2	CEBPG	P53567	514
GRPEL2	CHAC1	Q9BUX1	505
GRPEL2	PAM16	Q9Y3D7	503
GRPEL2	HSPA8	P11142	490
GRPEL2	DNAJC19	Q96DA6	462
GRPEL2	DNLZ	Q5SXM8	461
GRPEL2	RCBTB2	O95199	459
GRPEL2	CTNNAL1	Q9UBT7	453
GRPEL2	TRIB3	Q96RU7	453

IntAct

17 interactions, top by confidence:

A	B	Type	Score
GRPEL2	DBT	psi-mi:“MI:0914”(association)	0.710
GRPEL2	DBT	psi-mi:“MI:0915”(physical association)	0.710
GRPEL1	HSPA9	psi-mi:“MI:0914”(association)	0.670
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
OXLD1	NUDT19	psi-mi:“MI:0914”(association)	0.350
MRM1	KIAA0391	psi-mi:“MI:0914”(association)	0.350
GRPEL1	TPPP	psi-mi:“MI:0914”(association)	0.350
MRM1	PRORP	psi-mi:“MI:0914”(association)	0.350
OXLD1	PRORP	psi-mi:“MI:0914”(association)	0.350
SPX	ERI3	psi-mi:“MI:0914”(association)	0.350
DDX54	SYNCRIP	psi-mi:“MI:0914”(association)	0.350
GNLY	PRKCI	psi-mi:“MI:0914”(association)	0.350
FECH	GTPBP10	psi-mi:“MI:0914”(association)	0.350
GRPEL2	FAM83G	psi-mi:“MI:0914”(association)	0.350

BioGRID (43): GRPEL2 (Affinity Capture-MS), MUT (Affinity Capture-MS), DBT (Affinity Capture-MS), NDUFAF5 (Affinity Capture-MS), YES1 (Affinity Capture-MS), C7orf55 (Affinity Capture-MS), LYRM7 (Affinity Capture-MS), GRPEL2 (Affinity Capture-MS), GRPEL2 (Affinity Capture-MS), GRPEL2 (Affinity Capture-MS), GRPEL2 (Affinity Capture-MS), GRPEL2 (Affinity Capture-MS), DBT (Affinity Capture-MS), C7orf55 (Affinity Capture-MS), MUT (Affinity Capture-MS)

ESM2 similar proteins: A1A4J8, A5PK26, O35231, O88396, P19686, P19687, P36407, P48760, P97576, Q07617, Q0P5N5, Q15027, Q1JQC5, Q1L5Z9, Q32KL4, Q3SZC1, Q3UY23, Q4G069, Q4R380, Q502I6, Q5R435, Q5R8E4, Q5RA81, Q5U2X2, Q60443, Q6DKK2, Q6PBQ2, Q7SXA9, Q80VP5, Q80Y81, Q80ZX8, Q8BMS4, Q8BUI3, Q8C9A2, Q8CGS5, Q8CI66, Q8IWL3, Q8K2H4, Q8K3A0, Q8NFF5

Diamond homologs: A0K4S6, A0Q7F1, A1TLI0, A1UUC9, A1WX32, A3MNA1, A4IX27, A4JBR9, A4SQ26, A5IDK9, A5VNA6, A6U5E2, A6WVA7, A7HZ43, A7NCM8, A9AGC0, A9IGC0, A9ILE9, A9M7B6, B0CJ30, B0T367, B0TYF1, B0UT70, B1JW17, B2IDD9, B2SXC5, B3PZA4, B3Q970, B3R450, B4EDZ4, B5ZMX0, B6JCI1, B8ET77, B8F790, B8GXP4, B8IJD7, B9JZG5, C5BQ34, O08384, O32481

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GRPEL2	“form complex”	“TIM23 complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

419 predictions. Top by Δscore:

Variant	Effect	Δscore
5:149345613:GCAA:G	donor_gain	1.0000
5:149345617:G:GG	donor_gain	1.0000
5:149348264:T:A	acceptor_gain	1.0000
5:149348267:TTTAG:T	acceptor_loss	1.0000
5:149348269:TA:T	acceptor_loss	1.0000
5:149348270:A:AG	acceptor_gain	1.0000
5:149348270:AG:A	acceptor_gain	1.0000
5:149348270:AGG:A	acceptor_gain	1.0000
5:149348270:AGGG:A	acceptor_gain	1.0000
5:149348271:G:GA	acceptor_gain	1.0000
5:149348271:GG:G	acceptor_gain	1.0000
5:149348271:GGG:G	acceptor_gain	1.0000
5:149348271:GGGG:G	acceptor_gain	1.0000
5:149348271:GGGGA:G	acceptor_gain	1.0000
5:149348423:ACA:A	donor_gain	1.0000
5:149348424:CA:C	donor_gain	1.0000
5:149348424:CAGT:C	donor_loss	1.0000
5:149348425:AGT:A	donor_loss	1.0000
5:149348426:G:GG	donor_gain	1.0000
5:149349644:T:TA	acceptor_gain	1.0000
5:149349650:TCA:T	acceptor_loss	1.0000
5:149349651:CA:C	acceptor_loss	1.0000
5:149349652:AGG:A	acceptor_loss	1.0000
5:149349734:TGG:T	donor_loss	1.0000
5:149349736:G:A	donor_loss	1.0000
5:149349736:G:GG	donor_gain	1.0000
5:149349737:T:G	donor_loss	1.0000
5:149345614:C:T	donor_gain	0.9900
5:149345616:AGTAA:A	donor_loss	0.9900
5:149345617:G:GA	donor_loss	0.9900

AlphaMissense

1442 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:149349732:T:C	F104L	0.995
5:149349734:T:A	F104L	0.995
5:149349734:T:G	F104L	0.995
5:149349723:G:C	A101P	0.993
5:149351209:G:A	G202D	0.992
5:149350932:T:C	C110R	0.991
5:149349669:G:C	A83P	0.990
5:149350933:G:A	C110Y	0.990
5:149350934:T:G	C110W	0.990
5:149351211:T:G	Y203D	0.990
5:149351233:T:A	I210N	0.990
5:149351065:T:C	L154P	0.989
5:149350953:G:C	A117P	0.987
5:149351226:C:A	R208S	0.987
5:149351227:G:C	R208P	0.987
5:149351236:G:T	R211M	0.987
5:149350918:G:A	G105E	0.985
5:149351218:T:C	L205P	0.984
5:149349700:G:C	R93P	0.983
5:149351188:T:A	V195E	0.983
5:149350930:T:C	F109S	0.982
5:149351212:A:C	Y203S	0.982
5:149351233:T:G	I210S	0.982
5:149351092:T:C	L163P	0.981
5:149351233:T:C	I210T	0.981
5:149351236:G:C	R211T	0.981
5:149351242:C:A	A213D	0.981
5:149351237:G:C	R211S	0.980
5:149351237:G:T	R211S	0.980
5:149351208:G:C	G202R	0.977

dbSNP variants (sampled 300 via entrez): RS1000202482 (5:149350155 T>A,C), RS1000280045 (5:149346326 T>C), RS1000291378 (5:149346555 T>C), RS1001071984 (5:149345353 C>G), RS1001248314 (5:149352233 AT>A,ATT,ATTT), RS1001558648 (5:149349051 A>G), RS1001753970 (5:149346860 C>T), RS1001984265 (5:149350481 T>C), RS1002036980 (5:149343863 C>T), RS1002050635 (5:149348704 C>T), RS1002105758 (5:149344330 G>A), RS1002354570 (5:149350230 G>T), RS1002965234 (5:149347682 T>A), RS1003375569 (5:149348169 C>A,G,T), RS1003429528 (5:149348441 A>G)

Disease associations

OMIM: gene MIM:618545 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	3
sodium arsenite	decreases expression, increases expression	2
Leflunomide	increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bufotalin	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
perfluorooctanoic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	affects expression	1
K 7174	increases expression	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Atrazine	decreases expression	1
Cisplatin	increases expression	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	1
Hydrogen Peroxide	affects expression	1
Phenobarbital	affects expression	1
Plant Oils	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Tunicamycin	increases expression	1
Urethane	increases expression	1

Clinical trials (associated diseases)

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