LRR1

Summary

LRR1 (leucine rich repeat protein 1, HGNC:19742) is a protein-coding gene on chromosome 14q21.3, encoding Leucine-rich repeat protein 1 (Q96L50). Substrate recognition subunit of an ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

The protein encoded by this gene contains a leucine-rich repeat (LRR). It specifically interacts with TNFRSF9/4-1BB, a member of the tumor necrosis factor receptor (TNFR) superfamily. Overexpression of this gene suppresses the activation of NF-kappa B induced by TNFRSF9 or TNF receptor-associated factor 2 (TRAF2), which suggests that this protein is a negative regulator of TNFRSF9-mediated signaling cascades. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 122769 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 68 total
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_152329

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19742
Approved symbol	LRR1
Name	leucine rich repeat protein 1
Location	14q21.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC20689, LRR-1
Ensembl gene	ENSG00000165501
Ensembl biotype	protein_coding
OMIM	609193
Entrez	122769

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000298288, ENST00000318317, ENST00000540712, ENST00000554869, ENST00000557531, ENST00000879395

RefSeq mRNA: 2 — MANE Select: NM_152329 NM_152329, NM_203467

CCDS: CCDS9686, CCDS9687

Canonical transcript exons

ENST00000298288 — 4 exons

Exon	Start	End
ENSE00001345606	49598940	49599203
ENSE00001874102	49614256	49614672
ENSE00003604748	49602370	49602468
ENSE00003629017	49607400	49608121

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 92.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.3676 / max 110.7990, expressed in 1770 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139432	6.2495	1662
139433	4.8392	1343
139428	0.9144	515
139427	0.1331	77
139430	0.1267	24
139429	0.0897	15
139431	0.0150	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	92.95	gold quality
secondary oocyte	CL:0000655	90.53	gold quality
adult organism	UBERON:0007023	89.92	gold quality
mucosa of transverse colon	UBERON:0004991	89.71	gold quality
oocyte	CL:0000023	89.48	gold quality
left testis	UBERON:0004533	88.98	gold quality
right testis	UBERON:0004534	88.63	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.17	gold quality
testis	UBERON:0000473	88.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.59	gold quality
bone marrow	UBERON:0002371	85.73	gold quality
colonic mucosa	UBERON:0000317	85.59	gold quality
ventricular zone	UBERON:0003053	85.20	gold quality
mucosa of sigmoid colon	UBERON:0004993	85.08	gold quality
rectum	UBERON:0001052	84.38	gold quality
duodenum	UBERON:0002114	83.64	gold quality
embryo	UBERON:0000922	83.38	gold quality
ganglionic eminence	UBERON:0004023	83.38	gold quality
thymus	UBERON:0002370	83.30	gold quality
stromal cell of endometrium	CL:0002255	83.23	gold quality
sperm	CL:0000019	83.18	gold quality
leukocyte	CL:0000738	83.08	gold quality
monocyte	CL:0000576	82.94	gold quality
jejunal mucosa	UBERON:0000399	82.83	gold quality
granulocyte	CL:0000094	82.65	gold quality
vermiform appendix	UBERON:0001154	82.26	gold quality
trabecular bone tissue	UBERON:0002483	81.99	gold quality
transverse colon	UBERON:0001157	81.68	gold quality
smooth muscle tissue	UBERON:0001135	80.95	gold quality
large intestine	UBERON:0000059	80.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.66

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

21 targeting LRR1, 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-5193	100.00	67.26	1744
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-190B-3P	99.33	68.29	1382
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-3925-5P	99.21	67.90	1466
HSA-MIR-361-5P	98.95	70.16	1340
HSA-MIR-3145-5P	98.57	67.83	900
HSA-MIR-6784-3P	98.39	64.88	662
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-6847-5P	97.93	66.74	1808
HSA-MIR-6862-3P	97.92	64.86	531
HSA-MIR-3198	97.84	65.64	579
HSA-MIR-4309	97.84	65.45	588
HSA-MIR-3074-3P	97.83	67.26	922

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 2)

• Results identify the CRL2(LRR-1) ubiquitin ligase as a conserved regulator of Cip/Kip CKIs that promotes the degradation of C. elegans CKI-1 and human p21. (PMID:21074724)
• LRR1-mediated replisome disassembly promotes DNA replication by recycling replisome components. (PMID:34037657)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrr1	ENSDARG00000104448
mus_musculus	Lrr1	ENSMUSG00000034883
rattus_norvegicus	Lrr1	ENSRNOG00000004216
drosophila_melanogaster	Lrr47	FBGN0010398

Protein

Protein identifiers

Leucine-rich repeat protein 1 — Q96L50 (reviewed: Q96L50)

Alternative names: 4-1BB-mediated-signaling molecule, 4-1BBlrr, LRR-repeat protein 1, Peptidylprolyl isomerase-like 5

All UniProt accessions (4): A0A384MTQ0, Q96L50, G3V5H2, Q6P393

UniProt curated annotations — full annotation on UniProt →

Function. Substrate recognition subunit of an ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. ECS(LRR1) ubiquitinates MCM7 and promotes CMG replisome disassembly by VCP and chromatin extraction during S-phase. May negatively regulate the 4-1BB-mediated signaling cascades which result in the activation of NK-kappaB and JNK1.

Subunit / interactions. Component of the probable ECS(LRR1) E3 ubiquitin-protein ligase complex which contains CUL2, RBX1, Elongin BC complex and LRR1. Interacts with CUL2, RBX1, ELOB and ELOC.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitous. Maximal expression was seen in the heart and skeletal muscle and minimal expression seen in the kidney.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96L50-1	1, LRR-1a	yes
Q96L50-2	2, LRR-1b

RefSeq proteins (2): NP_689542, NP_982292 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR025875	Leu-rich_rpt_4	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR050216	LRR_domain-containing	Family
IPR057437	PIF1/LRR1_PH	Domain

Pfam: PF00560, PF12799, PF25344

UniProt features (16 total): repeat 7, sequence conflict 3, sequence variant 2, splice variant 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7PLO	ELECTRON MICROSCOPY	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96L50-F1	88.39	0.64

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
341–344	abolishes interaction with cul2 and rbx1.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 180 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_NEGATIVE_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, WEI_MYCN_TARGETS_WITH_E_BOX, FREAC3_01, WTGAAAT_UNKNOWN, GRE_C, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GATA1_04

GO Biological Process (2): protein ubiquitination (GO:0016567), intracellular signal transduction (GO:0035556)

GO Molecular Function (2): protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (2): nucleus (GO:0005634), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Metabolism of proteins	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification by small protein conjugation	1
intracellular anatomical structure	1
signal transduction	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1900 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRR1	NLRP1	Q9C000	820
LRR1	CUL2	Q13617	818
LRR1	RBX1	P62877	790
LRR1	ELOC	Q15369	774
LRR1	ELOB	Q15370	716
LRR1	ZYG11A	Q6WRX3	703
LRR1	ZYG11B	Q9C0D3	695
LRR1	TNFRSF9	Q07011	659
LRR1	TRAIP	Q9BWF2	647
LRR1	ZER1	Q7Z7L7	606
LRR1	FEM1B	Q9UK73	598
LRR1	MCM7	P33993	593
LRR1	WDHD1	O75717	578
LRR1	PPP1R7	Q15435	563
LRR1	MCM3	P25205	563

IntAct

70 interactions, top by confidence:

A	B	Type	Score
CUL2	VHL	psi-mi:“MI:0914”(association)	0.940
COPS2	GPS1	psi-mi:“MI:0914”(association)	0.860
COPS8	COPS2	psi-mi:“MI:0914”(association)	0.850
RELL2	OXSR1	psi-mi:“MI:0914”(association)	0.830
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
CUL2	COPS2	psi-mi:“MI:0914”(association)	0.640
TRIP13	LRR1	psi-mi:“MI:0915”(physical association)	0.560
MTUS2	LRR1	psi-mi:“MI:0915”(physical association)	0.560
LRR1	PNMA2	psi-mi:“MI:0915”(physical association)	0.560
LRR1	MTUS2	psi-mi:“MI:0915”(physical association)	0.560
PNMA2	LRR1	psi-mi:“MI:0915”(physical association)	0.560
LRR1	TRIP13	psi-mi:“MI:0915”(physical association)	0.560
PFKFB4	LRR1	psi-mi:“MI:0915”(physical association)	0.560
COPS5	KLHL18	psi-mi:“MI:0914”(association)	0.530
COPS3	HBB	psi-mi:“MI:0914”(association)	0.530
ZBTB38	IPO7	psi-mi:“MI:0914”(association)	0.530

BioGRID (91): LRR1 (Two-hybrid), LRR1 (Two-hybrid), LRR1 (Two-hybrid), LRR1 (Affinity Capture-MS), LRR1 (Affinity Capture-MS), LRR1 (Affinity Capture-MS), LRR1 (Affinity Capture-MS), LRR1 (Affinity Capture-MS), LRR1 (Affinity Capture-MS), LRR1 (Affinity Capture-MS), LRR1 (Affinity Capture-MS), LRR1 (Affinity Capture-MS), LRR1 (Affinity Capture-MS), LRR1 (Affinity Capture-MS), LRR1 (Affinity Capture-MS)

ESM2 similar proteins: A0JM56, A0JPI9, A4IHG1, A5PK13, D3YY91, F1ND48, O35125, Q13309, Q15813, Q24K06, Q32KP2, Q32KS0, Q32L08, Q32NT4, Q3KQF4, Q3KRC6, Q3UGP9, Q498T9, Q4U2V3, Q5BKY1, Q5DU41, Q5FVQ9, Q5PQJ7, Q5QJ74, Q5R8X9, Q5RBD9, Q5U378, Q66JT1, Q68F79, Q6GQN5, Q6NSJ5, Q6NU09, Q6P9F7, Q6WRX3, Q6ZNQ3, Q8C5W3, Q8CDN9, Q8CIV8, Q8IY45, Q8IZ02

Diamond homologs: D3YY91, Q96L50, A0A290U7C4, F4HT77, F4I594, F4J339, F4JNA9, F4JNB7, F4JT78, F4JT80, F4JT82, F4JWM0, F4KHH8, F4KHI3, I1GTC2, O23530, O64789, O82500, P0DKH6, P0DTS9, Q0WSX8, Q40392, Q9C5Q9, Q9C7X0, Q9CAK1, Q9FHE8, Q9FHE9, Q9FI14, Q9FT77, Q9SSN3, Q9SYC9, Q9SZ66, Q9SZ67, V9M2S5, V9M398

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 50 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
DNA Damage Recognition in GG-NER	8	78.8×	9e-12
Formation of TC-NER Pre-Incision Complex	8	58.3×	6e-11
Cargo recognition for clathrin-mediated endocytosis	7	25.3×	4e-07
Neddylation	11	18.0×	5e-10
Neutrophil degranulation	7	5.6×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of protein neddylation	7	148.9×	2e-12
protein neddylation	8	127.7×	2e-13

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	57
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1110 predictions. Top by Δscore:

Variant	Effect	Δscore
14:49600195:G:GT	donor_gain	1.0000
14:49602355:ATT:A	acceptor_gain	1.0000
14:49602355:ATTG:A	acceptor_gain	1.0000
14:49602357:T:A	acceptor_gain	1.0000
14:49602369:GCTAA:G	acceptor_gain	1.0000
14:49602355:A:AG	acceptor_gain	0.9900
14:49602356:T:G	acceptor_gain	0.9900
14:49602368:A:AG	acceptor_gain	0.9900
14:49602369:G:GG	acceptor_gain	0.9900
14:49602369:GCTA:G	acceptor_gain	0.9900
14:49602464:G:GG	donor_gain	0.9900
14:49602464:GTAAG:G	donor_loss	0.9900
14:49602465:TAAGG:T	donor_loss	0.9900
14:49602466:AAGG:A	donor_loss	0.9900
14:49602467:AGGT:A	donor_loss	0.9900
14:49602469:GTATG:G	donor_loss	0.9900
14:49602470:T:A	donor_loss	0.9900
14:49600215:GCCTT:G	donor_gain	0.9800
14:49602358:G:A	acceptor_gain	0.9800
14:49602365:T:G	acceptor_gain	0.9800
14:49602367:CA:C	acceptor_loss	0.9800
14:49602368:AGCT:A	acceptor_loss	0.9800
14:49602369:G:GC	acceptor_loss	0.9800
14:49602369:GCT:G	acceptor_gain	0.9800
14:49614251:AATAG:A	acceptor_gain	0.9800
14:49600237:G:GT	donor_gain	0.9700
14:49600456:A:G	donor_gain	0.9700
14:49608119:TAGGT:T	donor_loss	0.9700
14:49608120:AGGTA:A	donor_loss	0.9700
14:49608122:GT:G	donor_loss	0.9700

AlphaMissense

2719 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:49607593:T:C	L159P	0.993
14:49602428:T:A	V81D	0.992
14:49602421:G:C	A79P	0.990
14:49607731:T:C	L205P	0.989
14:49602431:G:C	R82P	0.988
14:49607662:T:C	L182S	0.984
14:49607737:T:C	L207P	0.981
14:49602434:T:C	L83S	0.980
14:49607653:T:A	L179H	0.978
14:49607593:T:A	L159H	0.977
14:49607815:T:C	L233P	0.977
14:49607747:T:A	N210K	0.976
14:49607747:T:G	N210K	0.976
14:49607825:C:A	N236K	0.976
14:49607825:C:G	N236K	0.976
14:49602422:C:A	A79D	0.975
14:49607722:T:A	L202H	0.975
14:49599035:T:G	C5W	0.973
14:49602403:T:C	F73L	0.971
14:49602405:T:A	F73L	0.971
14:49602405:T:G	F73L	0.971
14:49608029:T:A	N304K	0.971
14:49608029:T:G	N304K	0.971
14:49607809:T:C	L231S	0.969
14:49607572:T:C	F152S	0.968
14:49607678:C:A	N187K	0.968
14:49607678:C:G	N187K	0.968
14:49607899:T:C	L261S	0.968
14:49607593:T:G	L159R	0.966
14:49607800:T:A	L228H	0.966

dbSNP variants (sampled 300 via entrez): RS1000022014 (14:49604974 C>T), RS1000132013 (14:49611583 T>C), RS1000455421 (14:49597152 G>A), RS1000613711 (14:49601449 T>C), RS1000892549 (14:49605288 C>T), RS1001005691 (14:49613783 A>T), RS1001520286 (14:49597524 C>G), RS1001572134 (14:49597813 A>AT), RS1001616044 (14:49608160 A>T), RS1001688648 (14:49597996 G>T), RS1001777691 (14:49601848 C>A,T), RS1001879240 (14:49598679 T>G), RS1002253283 (14:49602026 A>G), RS1002387939 (14:49608294 T>C), RS1002416101 (14:49606401 C>T)

Disease associations

OMIM: gene MIM:609193 | 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
GCST009391_1978	Metabolite levels	8.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008534	tryptophan measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Cadmium Chloride	increases expression, decreases expression	2
dicrotophos	decreases expression	1
bisphenol A	decreases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	increases expression, affects cotreatment	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
phenethyl isothiocyanate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
Dasatinib	decreases expression	1
Sunitinib	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Azathioprine	decreases expression	1
Cadmium	increases expression	1
Calcitriol	decreases expression, affects cotreatment	1
Coumestrol	increases expression, affects cotreatment	1
Diazinon	increases methylation	1
Estradiol	increases expression	1
Lead	increases expression	1
Mustard Gas	decreases expression	1
Nickel	increases expression	1
Oxygen	decreases expression	1

Clinical trials (associated diseases)

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