TYSND1

Summary

TYSND1 (trypsin like peroxisomal matrix peptidase 1, HGNC:28531) is a protein-coding gene on chromosome 10q22.1, encoding Peroxisomal leader peptide-processing protease (Q2T9J0). Peroxisomal protease that mediates both the removal of the leader peptide from proteins containing a PTS2 target sequence and processes several PTS1-containing proteins.

This gene encodes a protease that removes the N-terminal peroxisomal targeting signal (PTS2) from proteins produced in the cytosol, thereby facilitating their import into the peroxisome. The encoded protein is also capable of removing the C-terminal peroxisomal targeting signal (PTS1) from proteins in the peroxisomal matrix. The full-length protein undergoes self-cleavage to produce shorter, potentially inactive, peptides. Alternative splicing results in multiple transcript variants for this gene.

Source: NCBI Gene 219743 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 78 total
• MANE Select transcript: NM_173555

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28531
Approved symbol	TYSND1
Name	trypsin like peroxisomal matrix peptidase 1
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC34695, NET41
Ensembl gene	ENSG00000156521
Ensembl biotype	protein_coding
OMIM	611017
Entrez	219743

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000287078, ENST00000335494, ENST00000479086, ENST00000494143, ENST00000883565, ENST00000883566, ENST00000936946, ENST00000936947, ENST00000953716

RefSeq mRNA: 2 — MANE Select: NM_173555 NM_001040273, NM_173555

CCDS: CCDS31213, CCDS31214

Canonical transcript exons

ENST00000287078 — 4 exons

Exon	Start	End
ENSE00001856391	70145421	70146700
ENSE00003466800	70137981	70140141
ENSE00003492151	70142668	70142853
ENSE00003579537	70143842	70143972

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 89.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.1862 / max 150.3216, expressed in 1698 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
109818	10.5738	1679
109817	1.5412	786
109819	0.0712	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	89.56	gold quality
right testis	UBERON:0004534	89.41	gold quality
testis	UBERON:0000473	87.65	gold quality
skin of abdomen	UBERON:0001416	85.92	gold quality
skin of leg	UBERON:0001511	85.69	gold quality
lower esophagus mucosa	UBERON:0035834	85.64	gold quality
mucosa of transverse colon	UBERON:0004991	85.36	gold quality
esophagus mucosa	UBERON:0002469	85.03	gold quality
granulocyte	CL:0000094	84.88	gold quality
zone of skin	UBERON:0000014	83.67	gold quality
right adrenal gland	UBERON:0001233	82.61	gold quality
right lobe of liver	UBERON:0001114	82.11	gold quality
right lobe of thyroid gland	UBERON:0001119	81.74	gold quality
left adrenal gland	UBERON:0001234	81.72	gold quality
left adrenal gland cortex	UBERON:0035825	81.64	gold quality
right adrenal gland cortex	UBERON:0035827	81.62	gold quality
right hemisphere of cerebellum	UBERON:0014890	81.40	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.04	gold quality
minor salivary gland	UBERON:0001830	80.99	gold quality
cerebellar hemisphere	UBERON:0002245	80.99	gold quality
right uterine tube	UBERON:0001302	80.97	gold quality
esophagus	UBERON:0001043	80.94	gold quality
ectocervix	UBERON:0012249	80.75	gold quality
cerebellar cortex	UBERON:0002129	80.72	gold quality
spleen	UBERON:0002106	80.42	gold quality
left lobe of thyroid gland	UBERON:0001120	80.26	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.25	gold quality
transverse colon	UBERON:0001157	80.22	gold quality
apex of heart	UBERON:0002098	80.17	gold quality
body of pancreas	UBERON:0001150	80.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.90

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF

miRNA regulators (miRDB)

54 targeting TYSND1, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6080	99.43	69.43	373
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-8077	99.17	66.67	862
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-4744	99.01	69.91	1581
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-5006-5P	98.79	66.92	1246

Literature-anchored findings (GeneRIF, showing 2)

• characterization of protease function and self-cleavage of mouse Tysnd1 (PMID:17255948)
• The proteolytic activity of oligomeric Tysnd1 is in turn controlled by self-cleavage of Tysnd1 and degradation of Tysnd1 cleavage products by PsLon. (PMID:22002062)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tysnd1	ENSDARG00000074895
mus_musculus	Tysnd1	ENSMUSG00000020087
rattus_norvegicus	Tysnd1	ENSRNOG00000024839
drosophila_melanogaster	CG3589	FBGN0035065

Protein

Protein identifiers

Peroxisomal leader peptide-processing protease — Q2T9J0 (reviewed: Q2T9J0)

Alternative names: Trypsin domain-containing protein 1

All UniProt accessions (1): Q2T9J0

UniProt curated annotations — full annotation on UniProt →

Function. Peroxisomal protease that mediates both the removal of the leader peptide from proteins containing a PTS2 target sequence and processes several PTS1-containing proteins. Catalyzes the processing of PTS1-proteins involved in the peroxisomal beta-oxidation of fatty acids.

Subunit / interactions. Homodimer. Forms a heterodimer with the C-terminal cleavage product (45 kDa form). Forms a heterodimer with the N-terminal cleavage product (15 kDa form). Interacts with PEX5. Interacts with LONP2.

Subcellular location. Peroxisome.

Post-translational modifications. Self-cleavage gives rise to an N-terminal 15-kDa fragment and C-terminal 45-kDa fragment upon import into the peroxisomes. The full-lengh TYSND1 is the active the proteolytic processing of PTS1- and PTS2-proteins and in self-cleavage, and intermolecular self-cleavage of TYSND1 down-regulates its protease activity.

Similarity. Belongs to the peptidase S1B family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q2T9J0-1	1	yes
Q2T9J0-2	2

RefSeq proteins (2): NP_001035363, NP_775826* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR017345	Pept_S1A_Tysnd1	Family
IPR039245	TYSND1/DEG15	Family

Pfam: PF13365

UniProt features (13 total): chain 3, active site 3, splice variant 2, sequence variant 1, mutagenesis site 1, sequence conflict 1, region of interest 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2T9J0-F1	83.46	0.55

Functional residue map

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

Catalytic / active sites (4): 372 (charge relay system); 408 (charge relay system); 481 (charge relay system); 110–111 (cleavage)

Mutagenesis-validated functional residues (1):

Position	Phenotype
481	abrogates the self-cleaving activity of tysnd1.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9033241	Peroxisomal protein import
R-HSA-9033500	TYSND1 cleaves peroxisomal proteins

MSigDB gene sets: 137 (showing top): GOBP_LIPID_MODIFICATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, GOBP_REGULATION_OF_FATTY_ACID_METABOLIC_PROCESS, PATIL_LIVER_CANCER, GTGCCTT_MIR506, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, CCANNAGRKGGC_UNKNOWN, GOBP_PROTEIN_MATURATION, AP1_Q4_01, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_REGULATION_OF_KETONE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, TGANTCA_AP1_C

GO Biological Process (3): proteolysis (GO:0006508), protein processing (GO:0016485), regulation of fatty acid beta-oxidation (GO:0031998)

GO Molecular Function (7): protease binding (GO:0002020), serine-type endopeptidase activity (GO:0004252), identical protein binding (GO:0042802), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (4): peroxisome (GO:0005777), peroxisomal matrix (GO:0005782), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein localization	1
Peroxisomal protein import	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein metabolic process	1
proteolysis	1
protein maturation	1
fatty acid beta-oxidation	1
regulation of fatty acid oxidation	1
regulation of lipid catabolic process	1
enzyme binding	1
endopeptidase activity	1
serine-type peptidase activity	1
protein binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
microbody	1
peroxisome	1
microbody lumen	1
cytoplasm	1

Protein interactions and networks

STRING

1758 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TYSND1	ACAA1	P09110	824
TYSND1	ACOX1	Q15067	792
TYSND1	LONP2	Q86WA8	718
TYSND1	PEX14	O75381	593
TYSND1	PEX5	P50542	575
TYSND1	PEX7	O00628	564
TYSND1	PEX19	P40855	547
TYSND1	PTGR3	Q8N4Q0	547
TYSND1	PEX6	Q13608	539
TYSND1	PEX10	O60683	508
TYSND1	GMEB2	Q9UKD1	490
TYSND1	CNEP1R1	Q8N9A8	482
TYSND1	GNPAT	O15228	478
TYSND1	ACAD11	Q709F0	475
TYSND1	DHRS7B	Q6IAN0	471

IntAct

37 interactions, top by confidence:

A	B	Type	Score
JOSD2	AHCYL1	psi-mi:“MI:0914”(association)	0.740
CAT	TYSND1	psi-mi:“MI:0403”(colocalization)	0.550
TEKT3	CLUH	psi-mi:“MI:0914”(association)	0.530
TYSND1	HSPA8	psi-mi:“MI:0914”(association)	0.530
rep	SBNO1	psi-mi:“MI:0914”(association)	0.530
VPS37D	CRTAP	psi-mi:“MI:0914”(association)	0.530
ARHGEF39	TYSND1	psi-mi:“MI:0915”(physical association)	0.500
	CAND2	psi-mi:“MI:0914”(association)	0.460
gag-pol	EIF3F	psi-mi:“MI:0914”(association)	0.460
CAT	NUDT19	psi-mi:“MI:0914”(association)	0.420
DCAKD	TYSND1	psi-mi:“MI:0915”(physical association)	0.400
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
JOSD2		psi-mi:“MI:0914”(association)	0.350
JOSD2	TRAPPC2	psi-mi:“MI:0914”(association)	0.350
rep	SBNO1	psi-mi:“MI:0914”(association)	0.350
PEX5	AGPS	psi-mi:“MI:0914”(association)	0.350
ATXN7L1	USP27X	psi-mi:“MI:0914”(association)	0.350
XXYLT1	PRMT3	psi-mi:“MI:0914”(association)	0.350
ARHGEF39	ACAA1	psi-mi:“MI:0914”(association)	0.350
GZMH	DENND11	psi-mi:“MI:0914”(association)	0.350
POLD3	ESYT2	psi-mi:“MI:0914”(association)	0.350
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
P2RY1	GPC4	psi-mi:“MI:0914”(association)	0.350
MFSD3	NME4	psi-mi:“MI:0914”(association)	0.350
MFSD6L	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (48): TYSND1 (Affinity Capture-MS), TYSND1 (Affinity Capture-MS), TYSND1 (Affinity Capture-MS), TYSND1 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), STUB1 (Affinity Capture-MS), ANKRD40 (Affinity Capture-MS), TYSND1 (Affinity Capture-MS), TYSND1 (Proximity Label-MS), TYSND1 (Affinity Capture-MS), TYSND1 (Affinity Capture-MS), TYSND1 (Affinity Capture-MS), TYSND1 (Affinity Capture-MS), TYSND1 (Affinity Capture-MS), TYSND1 (Affinity Capture-MS)

ESM2 similar proteins: A1A4I4, A5PKD8, A6NED2, A8MQ27, O35465, O60294, O75808, O94819, O95382, P70268, Q0MW30, Q14318, Q16512, Q2T9J0, Q32NY4, Q32P44, Q3B7U9, Q3MHW0, Q3U5Q7, Q3USL1, Q4R828, Q561R2, Q5EBM0, Q5EBP3, Q5PQP9, Q60806, Q63433, Q6PAT0, Q7T0L4, Q8BNW9, Q8BTU7, Q8BYR1, Q8IYL2, Q8N5A5, Q8NEP7, Q8VC03, Q8VHS5, Q8WXI3, Q91ZT7, Q96C12

Diamond homologs: Q2T9J0, Q9DBA6

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
TYSND1	“down-regulates activity”	TYSND1	cleavage
LONP2	“down-regulates quantity by destabilization”	TYSND1	cleavage
TYSND1	“up-regulates activity”	SCP2	cleavage
TYSND1	“up-regulates activity”	ACOX1	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Peroxisomal protein import	5	33.3×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	69
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

784 predictions. Top by Δscore:

Variant	Effect	Δscore
10:70140143:T:A	acceptor_loss	1.0000
10:70142678:T:A	donor_gain	1.0000
10:70140137:TATGC:T	acceptor_gain	0.9900
10:70140138:ATGC:A	acceptor_gain	0.9900
10:70140139:TGC:T	acceptor_gain	0.9900
10:70140142:C:CC	acceptor_gain	0.9900
10:70140154:C:CT	acceptor_gain	0.9900
10:70141969:CAATT:C	donor_gain	0.9900
10:70143968:CACTC:C	acceptor_gain	0.9900
10:70145419:A:AC	donor_gain	0.9900
10:70145420:C:CC	donor_gain	0.9900
10:70140140:GC:G	acceptor_gain	0.9800
10:70140141:CC:C	acceptor_gain	0.9800
10:70140145:T:C	acceptor_gain	0.9800
10:70140145:T:TC	acceptor_gain	0.9800
10:70140155:A:T	acceptor_gain	0.9800
10:70143970:CTC:C	acceptor_gain	0.9800
10:70145457:T:TA	donor_gain	0.9800
10:70145458:C:A	donor_gain	0.9800
10:70142662:GGTTA:G	donor_loss	0.9700
10:70142663:GTTAC:G	donor_loss	0.9700
10:70142664:TTA:T	donor_loss	0.9700
10:70142665:T:G	donor_loss	0.9700
10:70142666:A:C	donor_loss	0.9700
10:70142667:C:CG	donor_loss	0.9700
10:70142678:T:TA	donor_loss	0.9700
10:70143834:T:TA	donor_gain	0.9700
10:70146063:T:TA	donor_gain	0.9700
10:70145731:T:TA	donor_gain	0.9600
10:70145749:C:CT	donor_gain	0.9600

AlphaMissense

3595 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:70140077:G:C	S516R	0.994
10:70140077:G:T	S516R	0.994
10:70140079:T:G	S516R	0.994
10:70142729:A:C	C474W	0.993
10:70140083:G:C	N514K	0.992
10:70140083:G:T	N514K	0.992
10:70145477:A:C	C370W	0.992
10:70145855:G:C	S244R	0.992
10:70145855:G:T	S244R	0.992
10:70145857:T:G	S244R	0.992
10:70142708:A:C	S481R	0.991
10:70142708:A:T	S481R	0.991
10:70142710:T:G	S481R	0.991
10:70142742:A:G	L470P	0.989
10:70142828:A:C	F441L	0.989
10:70142828:A:T	F441L	0.989
10:70142830:A:G	F441L	0.989
10:70143911:C:G	A410P	0.986
10:70145909:G:C	F226L	0.986
10:70145909:G:T	F226L	0.986
10:70145911:A:G	F226L	0.986
10:70146032:A:C	F185L	0.986
10:70146032:A:T	F185L	0.986
10:70146034:A:G	F185L	0.986
10:70140072:G:T	P518H	0.985
10:70142668:C:G	G495R	0.985
10:70142730:C:T	C474Y	0.985
10:70142787:C:A	G455V	0.985
10:70145880:T:A	N236I	0.985
10:70143916:T:A	D408V	0.984

dbSNP variants (sampled 300 via entrez): RS1000063689 (10:70146300 C>T), RS1000374411 (10:70144232 G>A), RS1000794496 (10:70139050 T>C), RS1000825639 (10:70139250 T>C), RS1000843921 (10:70137560 GA>G), RS1001620411 (10:70142560 A>G,T), RS1002101705 (10:70148001 C>T), RS1002556909 (10:70141201 A>G), RS1002629415 (10:70142454 G>A,C), RS1002809058 (10:70145943 T>C,G), RS1002934500 (10:70141459 A>G), RS1002991277 (10:70146996 G>A), RS1003197408 (10:70145596 G>A,C), RS1003289880 (10:70141005 G>T), RS1003324107 (10:70141223 G>A)

Disease associations

OMIM: gene MIM:611017 | 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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	5
sodium arsenite	decreases expression, increases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
Benzo(a)pyrene	increases methylation, increases mutagenesis	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bufotalin	decreases expression	1
arsenite	affects binding, increases reaction	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
ferrous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	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
nutlin 3	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases 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	increases expression	1
Sunitinib	decreases expression	1
Arsenic	affects methylation	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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