GP2

Summary

GP2 (glycoprotein 2, HGNC:4441) is a protein-coding gene on chromosome 16p12.3, encoding Pancreatic secretory granule membrane major glycoprotein GP2 (P55259). Functions as an intestinal M-cell transcytotic receptor specific for type-I-piliated bacteria that participates in the mucosal immune response toward these bacteria.

This gene encodes an integral membrane protein that is secreted from intracellular zymogen granules and associates with the plasma membrane via glycosylphosphatidylinositol (GPI) linkage. The encoded protein binds pathogens such as enterobacteria, thereby playing an important role in the innate immune response. The C-terminus of this protein is related to the C-terminus of the protein encoded by the neighboring gene, uromodulin (UMOD). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 2813 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 95 total
• MANE Select transcript: NM_001502

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4441
Approved symbol	GP2
Name	glycoprotein 2
Location	16p12.3
Locus type	gene with protein product
Status	Approved
Aliases	ZAP75
Ensembl gene	ENSG00000169347
Ensembl biotype	protein_coding
OMIM	602977
Entrez	2813

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000302555, ENST00000341642, ENST00000381360, ENST00000381362, ENST00000572347, ENST00000572478, ENST00000573897, ENST00000574982, ENST00000575449, ENST00000575582, ENST00000575730, ENST00000888890, ENST00000888891, ENST00000888892

RefSeq mRNA: 4 — MANE Select: NM_001502 NM_001007240, NM_001007241, NM_001007242, NM_001502

CCDS: CCDS10582, CCDS42128, CCDS45432, CCDS45433

Canonical transcript exons

ENST00000302555 — 11 exons

Exon	Start	End
ENSE00001143327	20314657	20314701
ENSE00001143331	20315956	20316040
ENSE00001143337	20317213	20317375
ENSE00001143345	20318185	20318430
ENSE00001143373	20323816	20324256
ENSE00001386789	20326338	20326467
ENSE00001427760	20327467	20327513
ENSE00002632397	20309574	20311281
ENSE00003499651	20319620	20319768
ENSE00003620341	20322869	20322979
ENSE00003675190	20320262	20320473

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 99.98.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 40.1101 / max 69932.7509, expressed in 42 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156673	39.6417	38
156670	0.0908	9
156674	0.0588	3
156671	0.0549	7
156669	0.0511	3
156668	0.0464	3
156664	0.0456	4
156672	0.0248	4
156676	0.0247	1
156675	0.0233	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	99.98	gold quality
pancreas	UBERON:0001264	98.68	gold quality
islet of Langerhans	UBERON:0000006	96.92	gold quality
pancreatic ductal cell	CL:0002079	96.84	gold quality
epithelial cell of pancreas	CL:0000083	94.13	gold quality
metanephros cortex	UBERON:0010533	89.60	gold quality
gall bladder	UBERON:0002110	88.88	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	86.56	gold quality
sperm	CL:0000019	86.17	silver quality
male germ cell	CL:0000015	85.69	silver quality
duodenum	UBERON:0002114	84.82	gold quality
renal medulla	UBERON:0000362	84.08	gold quality
pylorus	UBERON:0001166	83.65	gold quality
prostate gland	UBERON:0002367	83.26	gold quality
trachea	UBERON:0003126	82.56	gold quality
type B pancreatic cell	CL:0000169	82.06	gold quality
body of stomach	UBERON:0001161	81.33	gold quality
olfactory bulb	UBERON:0002264	79.61	gold quality
adult mammalian kidney	UBERON:0000082	79.59	gold quality
cervix squamous epithelium	UBERON:0006922	79.37	gold quality
stomach	UBERON:0000945	77.49	gold quality
fundus of stomach	UBERON:0001160	77.03	gold quality
small intestine Peyer’s patch	UBERON:0003454	76.90	gold quality
nasal cavity mucosa	UBERON:0001826	76.34	gold quality
small intestine	UBERON:0002108	76.31	gold quality
diaphragm	UBERON:0001103	75.36	gold quality
rectum	UBERON:0001052	75.05	gold quality
lower esophagus mucosa	UBERON:0035834	74.36	gold quality
ectocervix	UBERON:0012249	73.60	gold quality
right lobe of liver	UBERON:0001114	73.52	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	19691.45
E-CURD-135	yes	705.98
E-CURD-119	yes	70.41
E-CURD-114	yes	11.79
E-GEOD-86618	yes	8.40
E-ENAD-27	yes	6.44
E-HCAD-31	no	3.18
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 17)

• GP2 binds to Type 1 fimbria, a bacterial adhesin that is commonly expressed by members of the Enterobacteriacae family. (PMID:19627615)
• glycoprotein 2 (GP2), specifically expressed on the apical plasma membrane of M cells among enterocytes, serves as a transcytotic receptor for mucosal antigens (PMID:19907495)
• This study represents the first detailed analysis of any variation in the GP2 gene and gives some support to the putative association of c.1275A>G with chronic pancreatitis disease protection. (PMID:19919903)
• Data suggest that GP2 alterations do not alter the risk for the development of chronic pancreatitis. (PMID:19959969)
• GP2 gene is unlikely to play a major role in the etiology of chronic pancreatitis. (PMID:20335779)
• GP2 is a binding partner of the scavenger receptor expressed on endothelial cells I (SREC-I) but not of SR-AI and SR-BI. Dendritic cells express SREC-I and also bind and internalize GP2. (PMID:21190681)
• A novel role for GP2 in immune regulation could provide a platform for new therapeutic interventions in the treatment of Crohn disease. (PMID:22891285)
• Anti-GP2 antibody positive CD patients had higher ASCA titres compared to seronegative cases. (PMID:23118780)
• Totals of 12.4% and 20.8% of Crohn’s disease patients were positive for IgA/IgG type of anti-GP2 and anti-CUZD1, respectively. Positivity for anti-pancreatic autoantibodies predicted a faster progression towards complicated disease course. (PMID:25968583)
• Data indicate the secretory granule membrane glycoprotein 2 as a marker for PDX1+/NKX6-1+ pancreatic progenitors (PPs). (PMID:28835709)
• Mucosal Autoimmunity to Cell-Bound GP2 Isoforms Is a Sensitive Marker in PSC and Associated With the Clinical Phenotype. (PMID:30233574)
• Novel anti-GP2 (isoforms 1 and 4) antibodies are associated with Crohn’s disease of the pouch in ulcerative colitis patients after ileal pouch-anal anastomosis. (PMID:30411391)
• Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer. (PMID:32581250)
• Antibodies Against Glycoprotein 2 Are Specific Biomarkers for Pediatric Crohn’s Disease. (PMID:32886311)
• Common Variants in NUS1 and GP2 Genes Contributed to the Risk of Gestational Diabetes Mellitus. (PMID:34326813)
• Structure of the decoy module of human glycoprotein 2 and uromodulin and its interaction with bacterial adhesin FimH. (PMID:35273390)
• According to human genome blasts for Build 35.1, this gene is located on 16p12 not 9q21 as described in this paper. (PMID:9605860)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:153932	ENSDARG00000052779
danio_rerio	si:ch211-226h7.5	ENSDARG00000074150
danio_rerio	si:ch211-226h7.6	ENSDARG00000076196
danio_rerio	umod	ENSDARG00000086117
danio_rerio	si:ch73-180n10.1	ENSDARG00000088794
danio_rerio	si:ch73-338o16.4	ENSDARG00000092778
danio_rerio	si:ch211-226h7.8	ENSDARG00000095409
danio_rerio	si:ch73-181m17.1	ENSDARG00000097080
danio_rerio	si:dkey-239b22.2	ENSDARG00000097826
danio_rerio	si:ch211-127b16.6	ENSDARG00000103650
danio_rerio	si:dkey-9l20.3	ENSDARG00000105341
danio_rerio	si:ch211-226h7.3	ENSDARG00000109626
danio_rerio		ENSDARG00000113315
mus_musculus	Gp2	ENSMUSG00000030954
rattus_norvegicus	Gp2	ENSRNOG00000015716

Paralogs (5): TECTB (ENSG00000119913), OIT3 (ENSG00000138315), UMOD (ENSG00000169344), ZPLD1 (ENSG00000170044), UMODL1 (ENSG00000177398)

Protein

Protein identifiers

Pancreatic secretory granule membrane major glycoprotein GP2 — P55259 (reviewed: P55259)

Alternative names: Pancreatic zymogen granule membrane protein GP-2, ZAP75

All UniProt accessions (6): P55259, I3L2Z7, I3L324, I3L3I2, I3L486, I3L4Y3

UniProt curated annotations — full annotation on UniProt →

Function. Functions as an intestinal M-cell transcytotic receptor specific for type-I-piliated bacteria that participates in the mucosal immune response toward these bacteria. At the apical membrane of M-cells it binds fimH, a protein of the bacteria type I pilus tip. Internalizes bound bacteria, like E.coli and S.typhimurium, from the lumen of the intestine and delivers them, through M-cells, to the underlying organized lymphoid follicles where they are captured by antigen-presenting dendritic cells to elicit a mucosal immune response.

Subunit / interactions. Interacts with SYCN. Interacts with bacterial adhesin fimH.

Subcellular location. Zymogen granule membrane. Secreted. Cell membrane. Apical cell membrane. Membrane raft. Endosome.

Tissue specificity. Expressed in pancreas (at protein level). Specifically expressed by M (microfold) cells which are atypical epithelial cells of the intestine (at protein level).

Post-translational modifications. N-glycosylated. Glycosylated Asn-65 may be required for interaction with bacterial adhesin fimH.

Domain organisation. Each ZP domain consists of an N-terminal (ZP-N) and C-terminal (ZP-C) region connected by a flexible linker; the linker allows the ZP domain to wrap around the ZP-C subdomain of the preceding subunit.

Isoforms (4)

UniProt ID	Names	Canonical?
P55259-1	1	yes
P55259-2	Beta
P55259-3	Alpha
P55259-4	2

RefSeq proteins (4): NP_001007241, NP_001007242, NP_001007243, NP_001493* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001507	ZP_dom	Domain
IPR017977	ZP_dom_CS	Conserved_site
IPR042235	ZP-C_dom	Homologous_superfamily
IPR048290	ZP_chr	Domain
IPR055355	ZP-C	Domain
IPR055356	ZP-N	Domain
IPR057774	D8C_UMOD/GP2/OIT3-like	Domain

Pfam: PF00100, PF23283, PF23344

UniProt features (57 total): disulfide bond 14, glycosylation site 10, strand 7, region of interest 6, sequence conflict 5, domain 3, splice variant 3, turn 2, helix 2, signal peptide 1, chain 1, lipid moiety-binding region 1, propeptide 1, mutagenesis site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7P6S	X-RAY DIFFRACTION	1.35
7P6T	X-RAY DIFFRACTION	1.4
7P6R	X-RAY DIFFRACTION	1.9
8XC5	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55259-F1	79.07	0.46

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): 512

Disulfide bonds (14): 48–59, 63–157, 85–172, 107–145, 113–177, 138–146, 190–200, 194–209, 211–241, 229–320, 261–284, 401–461, 422–477, 466–473

Glycosylation sites (10): 65, 88, 122, 134, 204, 216, 260, 291, 342, 362

Mutagenesis-validated functional residues (1):

Position	Phenotype
65	impaired interaction with fimh.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-163125	Post-translational modification: synthesis of GPI-anchored proteins
R-HSA-9925561	Developmental Lineage of Pancreatic Acinar Cells

MSigDB gene sets: 0 (showing top):

GO Biological Process (4): antigen transcytosis by M cells in mucosal-associated lymphoid tissue (GO:0002412), innate immune response (GO:0045087), neutrophil migration (GO:1990266), immune system process (GO:0002376)

GO Molecular Function (2): antigen binding (GO:0003823), protein binding (GO:0005515)

GO Cellular Component (13): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endosome (GO:0005768), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), apical plasma membrane (GO:0016324), zymogen granule membrane (GO:0042589), membrane raft (GO:0045121), extracellular exosome (GO:0070062), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Developmental Cell Lineages of the Exocrine Pancreas	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	2
membrane	2
antigen sampling by M cells in mucosal-associated lymphoid tissue	1
transcytosis	1
immune response	1
defense response to symbiont	1
granulocyte migration	1
biological_process	1
endomembrane system	1
cytoplasmic vesicle	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
apical part of cell	1
plasma membrane region	1
secretory granule membrane	1
zymogen granule	1
membrane microdomain	1
extracellular vesicle	1
cytoplasm	1
intracellular vesicle	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

1975 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GP2	GTPBP1	O00178	999
GP2	CD36	P16671	994
GP2	CD163	Q86VB7	974
GP2	NPC1	O15118	948
GP2	GP5	P40197	940
GP2	SV2C	Q496J9	919
GP2	SV2A	Q7L0J3	900
GP2	SV2B	Q7L1I2	900
GP2	GP6	Q9HCN6	820
GP2	ITIH4	Q14624	701
GP2	TMBIM4	Q9HC24	678
GP2	FURIN	P09958	669
GP2	MBTPS1	Q14703	667
GP2	GP9	P14770	651
GP2	ERVW-1	Q9UQF0	622

IntAct

3 interactions, top by confidence:

A	B	Type	Score
SOX30	GP2	psi-mi:“MI:0915”(physical association)	0.370
GP2	TSSK3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (5): GP2 (PCA), JAGN1 (Two-hybrid), GP2 (Affinity Capture-MS), SOX30 (Two-hybrid), TSSK3 (Two-hybrid)

ESM2 similar proteins: A0A0K2S4Q6, O19092, O19093, O46676, O46677, O46678, O76096, O89098, O97919, P01034, P07352, P09341, P10147, P13236, P13501, P14097, P14841, P16619, P19875, P19876, P30882, P46632, P47854, P50230, P50231, P55259, Q17QA1, Q2NKZ5, Q32KQ9, Q3TMX7, Q5EBF6, Q5GAN6, Q5I1Z0, Q5M7U7, Q61190, Q68AZ0, Q70IB3, Q711P4, Q86V40, Q8BVM4

Diamond homologs: A1Z877, B5DFC9, H9JIQ1, O08523, O75443, O88322, P07911, P10493, P19218, P25291, P27590, P34501, P41950, P48733, P55259, Q0KHY3, Q14112, Q28833, Q3U492, Q5R5C1, Q5ZQU0, Q6ZWJ8, Q70E20, Q862Z3, Q8CJ69, Q8TER0, Q91X17, Q9D733, Q9IBG7, Q9Y6R7, Q9YH85, P02845, Q8N8U9, Q66IR0, Q6DFV8, Q8N2E2, O08524, Q8R4V5, Q96PL2, Q5DID0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	8
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1444 predictions. Top by Δscore:

Variant	Effect	Δscore
16:20316041:C:CC	acceptor_gain	1.0000
16:20318179:CGTTA:C	donor_loss	1.0000
16:20318180:GTTAC:G	donor_loss	1.0000
16:20318181:TTA:T	donor_loss	1.0000
16:20318182:TA:T	donor_loss	1.0000
16:20318183:A:C	donor_loss	1.0000
16:20318184:C:CT	donor_loss	1.0000
16:20318207:T:TA	donor_gain	1.0000
16:20318426:GGGAA:G	acceptor_gain	1.0000
16:20318427:GGAA:G	acceptor_gain	1.0000
16:20318428:GAA:G	acceptor_gain	1.0000
16:20318429:AA:A	acceptor_gain	1.0000
16:20318430:AC:A	acceptor_loss	1.0000
16:20318431:C:CA	acceptor_loss	1.0000
16:20318431:C:CC	acceptor_gain	1.0000
16:20318432:T:C	acceptor_loss	1.0000
16:20319764:TTTCT:T	acceptor_gain	1.0000
16:20319767:CT:C	acceptor_gain	1.0000
16:20319771:T:C	acceptor_gain	1.0000
16:20319771:T:TC	acceptor_gain	1.0000
16:20319776:A:T	acceptor_gain	1.0000
16:20322975:TGGGT:T	acceptor_gain	1.0000
16:20322979:TC:T	acceptor_loss	1.0000
16:20322980:C:CC	acceptor_gain	1.0000
16:20322980:CTAG:C	acceptor_loss	1.0000
16:20322984:G:GC	acceptor_gain	1.0000
16:20322993:CA:C	acceptor_gain	1.0000
16:20326332:ACTT:A	donor_loss	1.0000
16:20326333:CTT:C	donor_loss	1.0000
16:20326334:TTA:T	donor_loss	1.0000

AlphaMissense

3520 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:20324075:C:A	W92C	0.997
16:20324075:C:G	W92C	0.997
16:20317289:A:C	F450C	0.996
16:20317295:A:C	F448C	0.994
16:20317310:A:G	F443S	0.994
16:20324013:C:G	C113S	0.994
16:20324014:A:T	C113S	0.994
16:20317309:G:C	F443L	0.993
16:20317309:G:T	F443L	0.993
16:20317310:A:C	F443C	0.993
16:20317311:A:G	F443L	0.993
16:20318373:G:C	F358L	0.993
16:20318373:G:T	F358L	0.993
16:20318375:A:G	F358L	0.993
16:20324067:A:C	F95C	0.993
16:20319677:C:G	C320S	0.992
16:20319678:A:T	C320S	0.992
16:20323991:C:A	W120C	0.992
16:20323991:C:G	W120C	0.992
16:20324077:A:G	W92R	0.992
16:20324077:A:T	W92R	0.992
16:20317264:G:C	F458L	0.991
16:20317264:G:T	F458L	0.991
16:20317266:A:G	F458L	0.991
16:20317294:G:C	F448L	0.990
16:20317294:G:T	F448L	0.990
16:20317296:A:G	F448L	0.990
16:20318374:A:C	F358C	0.990
16:20323820:G:C	C177W	0.990
16:20317288:A:C	F450L	0.989

dbSNP variants (sampled 300 via entrez): RS1000036330 (16:20322471 C>T), RS1000052957 (16:20328638 C>T), RS1000295620 (16:20326958 T>A), RS1000395598 (16:20327165 G>A), RS1000896870 (16:20316336 G>C), RS1001048760 (16:20309140 T>C), RS1001239653 (16:20320162 A>T), RS1001350284 (16:20322722 C>G), RS1002014374 (16:20325442 A>G), RS1002386552 (16:20314355 C>G,T), RS1002517113 (16:20320613 G>C), RS1002548063 (16:20320928 T>C), RS1002569597 (16:20310562 T>G), RS1002733608 (16:20314419 T>C), RS1002787060 (16:20323623 C>T)

Disease associations

OMIM: gene MIM:602977 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000649_18	Chronic kidney disease	1.000000e-20
GCST001415_5	Body mass index	1.000000e-08
GCST002461_23	Body mass index	6.000000e-07
GCST003659_2	Modified Stumvoll Insulin Sensitivity Index (BMI interaction)	3.000000e-07
GCST004904_181	Body mass index	1.000000e-17
GCST004904_97	Body mass index	8.000000e-12
GCST006190_84	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	6.000000e-08
GCST006191_2	Diastolic blood pressure x smoking status (ever vs never) interaction (1df test)	2.000000e-08
GCST007847_45	Type 2 diabetes	3.000000e-12
GCST010118_56	Type 2 diabetes	5.000000e-17
GCST010988_37	Adult body size	2.000000e-08
GCST010989_5	Body size at age 10	9.000000e-17
GCST90014023_3	Type 1 diabetes	2.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004471	insulin sensitivity measurement
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0009819	comparative body size at age 10, self-reported

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
Acetaminophen	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Hydralazine	affects cotreatment, increases expression	1
Smoke	increases expression	1
Urethane	decreases expression	1
Valproic Acid	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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