O60494 (CUBN_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cubilin

Alternative name(s):
460 kDa receptor
Intestinal intrinsic factor receptor
Intrinsic factor-cobalamin receptor
Intrinsic factor-vitamin B12 receptor

Gene names

Name:	CUBN
Synonyms:	IFCR

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	3623 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Cotransporter which plays a role in lipoprotein, vitamin and iron metabolism, by facilitating their uptake. Binds to ALB, MB, Kappa and lambda-light chains, TF, hemoglobin, GC, SCGB1A1, APOA1, high density lipoprotein, and the GIF-cobalamin complex. The binding of all ligands requires calcium. Serves as important transporter in several absorptive epithelia, including intestine, renal proximal tubules and embryonic yolk sac. Interaction with LRP2 mediates its trafficking throughout vesicles and facilitates the uptake of specific ligands like GC, hemoglobin, ALB, TF and SCGB1A1. Interaction with AMN controls its trafficking to the plasma membrane and facilitates endocytosis of ligands. May play an important role in the development of the peri-implantation embryo through internalization of APOA1 and cholesterol. Binds to LGALS3 at the maternal-fetal interface. Ref.1 Ref.4 Ref.5 Ref.6 Ref.7
Subunit structure	Interacts with LRP2 in a dual-receptor complex in a calcium-dependent manner. Component of the cubam complex composed of CUBN and AMN. The cubam complex can oligomerize and form cubam trimers. Found in a complex with PID1/PCLI1, LRP1 and CUBNI. Interacts with LRP1 and PID1/PCLI1. Ref.4 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9
Subcellular location	Endosome membrane; Peripheral membrane protein By similarity. Lysosome membrane; Peripheral membrane protein By similarity. Note: Colocalizes with AMN and LRP2 in the endocytotic apparatus of epithelial cells By similarity.
Tissue specificity	Expressed in kidney proximal tubule cells, placenta, visceral yolk-sac cells and in absorptive intestinal cells. Expressed in the epithelium of intestine and kidney.
Domain	The CUB domains 5 to 8 mediate binding to GIF and ALB. CUB domains 1 and 2 mediate interaction with LRP2.
Post-translational modification	The precursor is cleaved by a trans-Golgi proteinase furin. The result is a propeptide cleaved off. Ref.1 N-glycosylated. Ref.7 Ref.9
Involvement in disease	Recessive hereditary megaloblastic anemia 1 (RH-MGA1) [MIM:261100]: Due to selective malabsorption of vitamin B12. Defects in vitamin B12 absorption lead to impaired function of thymidine synthase. As a consequence DNA synthesis is interrupted. Rapidly dividing cells involved in erythropoiesis are particularly affected. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10 Ref.11
Sequence similarities	Contains 27 CUB domains. Contains 7 EGF-like domains.

Ontologies

Keywords
Biological process	Cholesterol metabolism Endocytosis Lipid metabolism Protein transport Steroid metabolism Sterol metabolism Transport
Cellular component	Endosome Lysosome Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	EGF-like domain Repeat Signal
Ligand	Calcium Cobalamin Cobalt Metal-binding
Molecular function	Receptor
PTM	Cleavage on pair of basic residues Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	cholesterol metabolic process Inferred from electronic annotation. Source: UniProtKB-KW cobalamin transport Traceable author statement Ref.10. Source: ProtInc lipoprotein metabolic process Traceable author statement. Source: Reactome lipoprotein transport Inferred from electronic annotation. Source: Compara receptor-mediated endocytosis Non-traceable author statement PubMed 11994745. Source: UniProtKB tissue homeostasis Non-traceable author statement PubMed 11994745. Source: UniProtKB vitamin D metabolic process Traceable author statement. Source: Reactome
Cellular_component	Golgi apparatus Inferred from electronic annotation. Source: Compara apical plasma membrane Inferred from electronic annotation. Source: Compara brush border membrane Non-traceable author statement PubMed 11994745. Source: UniProtKB coated pit Inferred from electronic annotation. Source: Compara cytosol Traceable author statement. Source: Reactome endocytic vesicle Inferred from electronic annotation. Source: Compara endoplasmic reticulum Inferred from electronic annotation. Source: Compara endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell extrinsic to external side of plasma membrane Non-traceable author statement PubMed 11994745. Source: UniProtKB lysosomal lumen Traceable author statement. Source: Reactome lysosomal membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	calcium ion binding Inferred from electronic annotation. Source: InterPro cobalamin binding Inferred from electronic annotation. Source: UniProtKB-KW protein homodimerization activity Inferred from direct assay PubMed 10552972. Source: UniProtKB receptor activity Traceable author statement Ref.10. Source: ProtInc transporter activity Traceable author statement PubMed 9478979. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 23

23

Potential

Propeptide

24 – 35

12

Removed in mature form

PRO_0000046072

Chain

36 – 3623

3588

Cubilin

PRO_0000046073

Regions

Domain

132 – 168

37

EGF-like 1

Domain

170 – 211

42

EGF-like 2; calcium-binding Potential

Domain

263 – 304

42

EGF-like 3; calcium-binding Potential

Domain

305 – 348

44

EGF-like 4; calcium-binding Potential

Domain

349 – 385

37

EGF-like 5

Domain

395 – 430

36

EGF-like 6

Domain

432 – 468

37

EGF-like 7; calcium-binding Potential

Domain

474 – 586

113

CUB 1

Domain

590 – 702

113

CUB 2

Domain

708 – 816

109

CUB 3

Domain

816 – 928

113

CUB 4

Domain

932 – 1042

111

CUB 5

Domain

1048 – 1161

114

CUB 6

Domain

1165 – 1277

113

CUB 7

Domain

1278 – 1389

112

CUB 8

Domain

1391 – 1506

116

CUB 9

Domain

1510 – 1619

110

CUB 10

Domain

1620 – 1734

115

CUB 11

Domain

1738 – 1850

113

CUB 12

Domain

1852 – 1963

112

CUB 13

Domain

1978 – 2091

114

CUB 14

Domain

2092 – 2213

122

CUB 15

Domain

2217 – 2334

118

CUB 16

Domain

2336 – 2448

113

CUB 17

Domain

2452 – 2565

114

CUB 18

Domain

2570 – 2687

118

CUB 19

Domain

2689 – 2801

113

CUB 20

Domain

2805 – 2919

115

CUB 21

Domain

2920 – 3035

116

CUB 22

Domain

3037 – 3150

114

CUB 23

Domain

3157 – 3274

118

CUB 24

Domain

3278 – 3393

116

CUB 25

Domain

3395 – 3507

113

CUB 26

Domain

3511 – 3623

113

CUB 27

Sites

Metal binding

980

1

Calcium 1

Metal binding

988

1

Calcium 1

Metal binding

1027

1

Calcium 1

Metal binding

1029

1

Calcium 1

Metal binding

1030

1

Calcium 1; via carbonyl oxygen

Metal binding

1096

1

Calcium 2

Metal binding

1105

1

Calcium 2

Metal binding

1146

1

Calcium 2

Metal binding

1148

1

Calcium 2; via carbonyl oxygen

Metal binding

1149

1

Calcium 2; via carbonyl oxygen

Metal binding

1213

1

Calcium 3

Metal binding

1221

1

Calcium 3

Metal binding

1262

1

Calcium 3

Metal binding

1264

1

Calcium 3; via carbonyl oxygen

Metal binding

1265

1

Calcium 3; via carbonyl oxygen

Metal binding

1328

1

Calcium 4

Metal binding

1336

1

Calcium 4

Metal binding

1373

1

Calcium 4

Metal binding

1375

1

Calcium 4; via carbonyl oxygen

Site

35 – 36

2

Cleavage; by furin Potential

Amino acid modifications

Glycosylation

3

1

N-linked (GlcNAc...) Potential

Glycosylation

105

1

N-linked (GlcNAc...) Potential

Glycosylation

428

1

N-linked (GlcNAc...) Potential

Glycosylation

482

1

N-linked (GlcNAc...) Potential

Glycosylation

711

1

N-linked (GlcNAc...) Potential

Glycosylation

749

1

N-linked (GlcNAc...) Potential

Glycosylation

781

1

N-linked (GlcNAc...) Potential

Glycosylation

857

1

N-linked (GlcNAc...) Potential

Glycosylation

957

1

N-linked (GlcNAc...) Potential

Glycosylation

984

1

N-linked (GlcNAc...) Ref.9

Glycosylation

1092

1

N-linked (GlcNAc...) Ref.9

Glycosylation

1168

1

N-linked (GlcNAc...) Ref.9

Glycosylation

1217

1

N-linked (GlcNAc...) Ref.9

Glycosylation

1285

1

N-linked (GlcNAc...) Ref.9

Glycosylation

1307

1

N-linked (GlcNAc...) Ref.9

Glycosylation

1319

1

N-linked (GlcNAc...) Ref.9

Glycosylation

1332

1

N-linked (GlcNAc...) Ref.9

Glycosylation

1500

1

N-linked (GlcNAc...) Potential

Glycosylation

1551

1

N-linked (GlcNAc...) Potential

Glycosylation

1646

1

N-linked (GlcNAc...) Potential

Glycosylation

1802

1

N-linked (GlcNAc...) Potential

Glycosylation

1819

1

N-linked (GlcNAc...) Potential

Glycosylation

1885

1

N-linked (GlcNAc...) Potential

Glycosylation

2085

1

N-linked (GlcNAc...) Potential

Glycosylation

2117

1

N-linked (GlcNAc...) Potential

Glycosylation

2274

1

N-linked (GlcNAc...) Potential

Glycosylation

2386

1

N-linked (GlcNAc...) Potential

Glycosylation

2400

1

N-linked (GlcNAc...) Potential

Glycosylation

2531

1

N-linked (GlcNAc...) Potential

Glycosylation

2581

1

N-linked (GlcNAc...) Potential

Glycosylation

2592

1

N-linked (GlcNAc...) Potential

Glycosylation

2610

1

N-linked (GlcNAc...) Potential

Glycosylation

2813

1

N-linked (GlcNAc...) Potential

Glycosylation

2923

1

N-linked (GlcNAc...) Potential

Glycosylation

2945

1

N-linked (GlcNAc...) Potential

Glycosylation

3042

1

N-linked (GlcNAc...) Potential

Glycosylation

3103

1

N-linked (GlcNAc...) Potential

Glycosylation

3125

1

N-linked (GlcNAc...) Potential

Glycosylation

3165

1

N-linked (GlcNAc...) Potential

Glycosylation

3268

1

N-linked (GlcNAc...) Potential

Glycosylation

3283

1

N-linked (GlcNAc...) Potential

Glycosylation

3290

1

N-linked (GlcNAc...) Potential

Glycosylation

3295

1

N-linked (GlcNAc...) Potential

Glycosylation

3357

1

N-linked (GlcNAc...) Potential

Glycosylation

3430

1

N-linked (GlcNAc...) Potential

Glycosylation

3457

1

N-linked (GlcNAc...) Potential

Glycosylation

3533

1

N-linked (GlcNAc...) Potential

Glycosylation

3576

1

N-linked (GlcNAc...) Potential

Disulfide bond

136 ↔ 147

By similarity

Disulfide bond

141 ↔ 156

By similarity

Disulfide bond

158 ↔ 167

By similarity

Disulfide bond

174 ↔ 190

By similarity

Disulfide bond

184 ↔ 199

By similarity

Disulfide bond

201 ↔ 210

By similarity

Disulfide bond

267 ↔ 280

By similarity

Disulfide bond

274 ↔ 289

By similarity

Disulfide bond

292 ↔ 303

By similarity

Disulfide bond

353 ↔ 366

By similarity

Disulfide bond

360 ↔ 376

By similarity

Disulfide bond

399 ↔ 409

By similarity

Disulfide bond

404 ↔ 418

By similarity

Disulfide bond

420 ↔ 429

By similarity

Disulfide bond

436 ↔ 447

By similarity

Disulfide bond

441 ↔ 456

By similarity

Disulfide bond

458 ↔ 467

By similarity

Disulfide bond

474 ↔ 500

By similarity

Disulfide bond

527 ↔ 549

By similarity

Disulfide bond

590 ↔ 616

By similarity

Disulfide bond

643 ↔ 665

By similarity

Disulfide bond

708 ↔ 734

By similarity

Disulfide bond

869 ↔ 891

By similarity

Disulfide bond

932 ↔ 958

Ref.9

Disulfide bond

985 ↔ 1005

Ref.9

Disulfide bond

1048 ↔ 1074

Ref.9

Disulfide bond

1165 ↔ 1191

Ref.9

Disulfide bond

1218 ↔ 1240

Ref.9

Disulfide bond

1278 ↔ 1306

Ref.9

Disulfide bond

1333 ↔ 1351

Ref.9

Disulfide bond

1391 ↔ 1417

By similarity

Disulfide bond

1444 ↔ 1466

By similarity

Disulfide bond

1510 ↔ 1536

By similarity

Disulfide bond

1563 ↔ 1581

By similarity

Disulfide bond

1620 ↔ 1647

By similarity

Disulfide bond

1675 ↔ 1697

By similarity

Disulfide bond

1738 ↔ 1764

By similarity

Disulfide bond

1791 ↔ 1812

By similarity

Disulfide bond

1905 ↔ 1927

By similarity

Disulfide bond

1978 ↔ 2006

By similarity

Disulfide bond

2032 ↔ 2054

By similarity

Disulfide bond

2092 ↔ 2118

By similarity

Disulfide bond

2217 ↔ 2247

By similarity

Disulfide bond

2275 ↔ 2297

By similarity

Disulfide bond

2336 ↔ 2363

By similarity

Disulfide bond

2390 ↔ 2411

By similarity

Disulfide bond

2452 ↔ 2478

By similarity

Disulfide bond

2505 ↔ 2527

By similarity

Disulfide bond

2570 ↔ 2599

By similarity

Disulfide bond

2628 ↔ 2649

By similarity

Disulfide bond

2689 ↔ 2715

By similarity

Disulfide bond

2742 ↔ 2764

By similarity

Disulfide bond

2805 ↔ 2831

By similarity

Disulfide bond

2860 ↔ 2883

By similarity

Disulfide bond

2920 ↔ 2946

By similarity

Disulfide bond

2977 ↔ 2999

By similarity

Disulfide bond

3037 ↔ 3064

By similarity

Disulfide bond

3091 ↔ 3113

By similarity

Disulfide bond

3157 ↔ 3185

By similarity

Disulfide bond

3215 ↔ 3237

By similarity

Disulfide bond

3278 ↔ 3306

By similarity

Disulfide bond

3332 ↔ 3354

By similarity

Disulfide bond

3395 ↔ 3421

By similarity

Disulfide bond

3448 ↔ 3470

By similarity

Disulfide bond

3511 ↔ 3537

By similarity

Disulfide bond

3564 ↔ 3586

By similarity

Natural variations

Natural variant

66

1

G → R.
Corresponds to variant rs12259370 [ dbSNP | Ensembl ].

VAR_047443

Natural variant

124

1

F → I. Ref.10
Corresponds to variant rs1801220 [ dbSNP | Ensembl ].

VAR_025284

Natural variant

253

1

F → S. Ref.1 Ref.10
Corresponds to variant rs1801222 [ dbSNP | Ensembl ].

VAR_025285

Natural variant

335

1

A → T.
Corresponds to variant rs57335729 [ dbSNP | Ensembl ].

VAR_061154

Natural variant

389

1

P → T. Ref.10
Corresponds to variant rs1801224 [ dbSNP | Ensembl ].

VAR_025286

Natural variant

504

1

I → M.
Corresponds to variant rs2228053 [ dbSNP | Ensembl ].

VAR_047444

Natural variant

730

1

H → Y.
Corresponds to variant rs7905349 [ dbSNP | Ensembl ].

VAR_047445

Natural variant

786

1

H → Q in a breast cancer sample; somatic mutation. Ref.12

VAR_035829

Natural variant

969

1

L → V.
Corresponds to variant rs11254354 [ dbSNP | Ensembl ].

VAR_047446

Natural variant

1032

1

Y → H. Ref.10
Corresponds to variant rs1801227 [ dbSNP | Ensembl ].

VAR_025287

Natural variant

1297

1

P → L in RH-MGA1; decreases strongly the GIF binding affinity. Ref.10 Ref.11
Corresponds to variant rs28939699 [ dbSNP | Ensembl ].

VAR_025288

Natural variant

1545

1

N → Y. Ref.1 Ref.10

VAR_025289

Natural variant

1559

1

P → S. Ref.10
Corresponds to variant rs1801231 [ dbSNP | Ensembl ].

VAR_025290

Natural variant

1769

1

V → I. Ref.1 Ref.10

VAR_025291

Natural variant

1775

1

R → W.
Corresponds to variant rs1276708 [ dbSNP | Ensembl ].

VAR_047447

Natural variant

1840

1

G → S.
Corresponds to variant rs2271462 [ dbSNP | Ensembl ].

VAR_047448

Natural variant

1935

1

S → G.
Corresponds to variant rs41289305 [ dbSNP | Ensembl ].

VAR_047449

Natural variant

1971

1

P → T.
Corresponds to variant rs2356590 [ dbSNP | Ensembl ].

VAR_047450

Natural variant

2153

1

L → F. Ref.10

VAR_025292

Natural variant

2162

1

C → Y. Ref.1
Corresponds to variant rs1276712 [ dbSNP | Ensembl ].

VAR_025293

Natural variant

2252

1

A → V in a colorectal cancer sample; somatic mutation. Ref.12

VAR_035830

Natural variant

2263

1

F → C.
Corresponds to variant rs2271460 [ dbSNP | Ensembl ].

VAR_047451

Natural variant

2444

1

R → Q.
Corresponds to variant rs11254274 [ dbSNP | Ensembl ].

VAR_047452

Natural variant

2575

1

P → R. Ref.10
Corresponds to variant rs3740168 [ dbSNP | Ensembl ].

VAR_025294

Natural variant

2691

1

G → R. Ref.10
Corresponds to variant rs1801237 [ dbSNP | Ensembl ].

VAR_025295

Natural variant

2717

1

S → W. Ref.1
Corresponds to variant rs2796835 [ dbSNP | Ensembl ].

VAR_025296

Natural variant

2879

1

L → I. Ref.10
Corresponds to variant rs45474496 [ dbSNP | Ensembl ].

VAR_025297

Natural variant

2914

1

A → V in a breast cancer sample; somatic mutation. Ref.12
Corresponds to variant rs45551835 [ dbSNP | Ensembl ].

VAR_035831

Natural variant

2968

1

E → Q.
Corresponds to variant rs45569534 [ dbSNP | Ensembl ].

VAR_047453

Natural variant

2984

1

I → V. Ref.10
Corresponds to variant rs1801239 [ dbSNP | Ensembl ].

VAR_025298

Natural variant

3002

1

E → G. Ref.10
Corresponds to variant rs1801240 [ dbSNP | Ensembl ].

VAR_025299

Natural variant

3189

1

I → V in a breast cancer sample; somatic mutation. Ref.12

VAR_035832

Natural variant

3258

1

S → G Found in a renal cell carcinoma case; somatic mutation. Ref.13

VAR_064704

Natural variant

3422

1

T → I. Ref.10
Corresponds to variant rs1801230 [ dbSNP | Ensembl ].

VAR_025300

Natural variant

3432

1

T → S.
Corresponds to variant rs7898873 [ dbSNP | Ensembl ].

VAR_055714

Natural variant

3552

1

N → K. Ref.10
Corresponds to variant rs1801232 [ dbSNP | Ensembl ].

VAR_025301

Experimental info

Sequence conflict

25

1

A → R in AAC82612. Ref.1

Sequence conflict

146

1

T → N in AAC82612. Ref.1

Secondary structure

1

.

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3623

Helix Strand Turn

Details...

Beta strand

938 – 942

5

Beta strand

959 – 963

5

Beta strand

966 – 972

7

Beta strand

987 – 993

7

Beta strand

997 – 1004

8

Beta strand

1016 – 1025

10

Beta strand

1038 – 1046

9

Beta strand

1048 – 1052

5

Turn

1062 – 1065

4

Beta strand

1073 – 1078

6

Beta strand

1087 – 1094

8

Beta strand

1104 – 1114

11

Beta strand

1119 – 1123

5

Beta strand

1125 – 1127

3

Beta strand

1135 – 1137

3

Beta strand

1139 – 1144

6

Beta strand

1153 – 1159

7

Beta strand

1171 – 1177

7

Turn

1179 – 1182

4

Beta strand

1190 – 1195

6

Beta strand

1203 – 1209

7

Beta strand

1220 – 1230

11

Beta strand

1233 – 1239

7

Beta strand

1251 – 1253

3

Beta strand

1255 – 1260

6

Beta strand

1271 – 1276

6

Beta strand

1279 – 1283

5

Beta strand

1287 – 1292

6

Turn

1294 – 1297

4

Beta strand

1305 – 1311

7

Beta strand

1319 – 1326

8

Turn

1331 – 1334

4

Beta strand

1335 – 1342

8

Beta strand

1345 – 1350

6

Beta strand

1362 – 1371

10

Beta strand

1381 – 1386

6

Sequences

	Sequence		Length	Mass (Da)
	O60494 [UniParc]. Last modified November 2, 2010. Version 5. Checksum: 8D602663C6D4751F	FASTA	3,623	398,736
	10 20 30 40 50 60 MMNMSLPFLW SLLTLLIFAE VNGEAGELEL QRQKRSINLQ QPRMATERGN LVFLTGSAQN 70 80 90 100 110 120 IEFRTGSLGK IKLNDEDLSE CLHQIQKNKE DIIELKGSAI GLPQNISSQI YQLNSKLVDL 130 140 150 160 170 180 ERKFQGLQQT VDKKVCSSNP CQNGGTCLNL HDSFFCICPP QWKGPLCSAD VNECEIYSGT 190 200 210 220 230 240 PLSCQNGGTC VNTMGSYSCH CPPETYGPQC ASKYDDCEGG SVARCVHGIC EDLMREQAGE 250 260 270 280 290 300 PKYSCVCDAG WMFSPNSPAC TLDRDECSFQ PGPCSTLVQC FNTQGSFYCG ACPTGWQGNG 310 320 330 340 350 360 YICEDINECE INNGGCSVAP PVECVNTPGS SHCQACPPGY QGDGRVCTLT DICSVSNGGC 370 380 390 400 410 420 HPDASCSSTL GSLPLCTCLP GYTGNGYGPN GCVQLSNICL SHPCLNGQCI DTVSGYFCKC 430 440 450 460 470 480 DSGWTGVNCT ENINECLSNP CLNGGTCVDG VDSFSCECTR LWTGALCQVP QQVCGESLSG 490 500 510 520 530 540 INGSFSYRSP DVGYVHDVNC FWVIKTEMGK VLRITFTFFR LESMDNCPHE FLQVYDGDSS 550 560 570 580 590 600 SAFQLGRFCG SSLPHELLSS DNALYFHLYS EHLRNGRGFT VRWETQQPEC GGILTGPYGS 610 620 630 640 650 660 IKSPGYPGNY PPGRDCVWIV VTSPDLLVTF TFGTLSLEHH DDCNKDYLEI RDGPLYQDPL 670 680 690 700 710 720 LGKFCTTFSV PPLQTTGPFA RIHFHSDSQI SDQGFHITYL TSPSDLRCGG NYTDPEGELF 730 740 750 760 770 780 LPELSGPFTH TRQCVYMMKQ PQGEQIQINF THVELQCQSD SSQNYIEVRD GETLLGKVCG 790 800 810 820 830 840 NGTISHIKSI TNSVWIRFKI DASVEKASFR AVYQVACGDE LTGEGVIRSP FFPNVYPGER 850 860 870 880 890 900 TCRWTIHQPQ SQVILLNFTV FEIGSSAHCE TDYVEIGSSS ILGSPENKKY CGTDIPSFIT 910 920 930 940 950 960 SVYNFLYVTF VKSSSTENHG FMAKFSAEDL ACGEILTEST GTIQSPGHPN VYPHGINCTW 970 980 990 1000 1010 1020 HILVQPNHLI HLMFETFHLE FHYNCTNDYL EVYDTDSETS LGRYCGKSIP PSLTSSGNSL 1030 1040 1050 1060 1070 1080 MLVFVTDSDL AYEGFLINYE AISAATACLQ DYTDDLGTFT SPNFPNNYPN NWECIYRITV 1090 1100 1110 1120 1130 1140 RTGQLIAVHF TNFSLEEAIG NYYTDFLEIR DGGYEKSPLL GIFYGSNLPP TIISHSNKLW 1150 1160 1170 1180 1190 1200 LKFKSDQIDT RSGFSAYWDG SSTGCGGNLT TSSGTFISPN YPMPYYHSSE CYWWLKSSHG 1210 1220 1230 1240 1250 1260 SAFELEFKDF HLEHHPNCTL DYLAVYDGPS SNSHLLTQLC GDEKPPLIRS SGDSMFIKLR 1270 1280 1290 1300 1310 1320 TDEGQQGRGF KAEYRQTCEN VVIVNQTYGI LESIGYPNPY SENQHCNWTI RATTGNTVNY 1330 1340 1350 1360 1370 1380 TFLAFDLEHH INCSTDYLEL YDGPRQMGRY CGVDLPPPGS TTSSKLQVLL LTDGVGRREK 1390 1400 1410 1420 1430 1440 GFQMQWFVYG CGGELSGATG SFSSPGFPNR YPPNKECIWY IRTDPGSSIQ LTIHDFDVEY 1450 1460 1470 1480 1490 1500 HSRCNFDVLE IYGGPDFHSP RIAQLCTQRS PENPMQVSST GNELAIRFKT DLSINGRGFN 1510 1520 1530 1540 1550 1560 ASWQAVTGGC GGIFQAPSGE IHSPNYPSPY RSNTDCSWVI RVDRNHRVLL NFTDFDLEPQ 1570 1580 1590 1600 1610 1620 DSCIMAYDGL SSTMSRLART CGREQLANPI VSSGNSLFLR FQSGPSRQNR GFRAQFRQAC 1630 1640 1650 1660 1670 1680 GGHILTSSFD TVSSPRFPAN YPNNQNCSWI IQAQPPLNHI TLSFTHFELE RSTTCARDFV 1690 1700 1710 1720 1730 1740 EILDGGHEDA PLRGRYCGTD MPHPITSFSS ALTLRFVSDS SISAGGFHTT VTASVSACGG 1750 1760 1770 1780 1790 1800 TFYMAEGIFN SPGYPDIYPP NVECVWNIVS SPGNRLQLSF ISFQLEDSQD CSRDFVEIRE 1810 1820 1830 1840 1850 1860 GNATGHLVGR YCGNSFPLNY SSIVGHTLWV RFISDGSGSG TGFQATFMKI FGNDNIVGTH 1870 1880 1890 1900 1910 1920 GKVASPFWPE NYPHNSNYQW TVNVNASHVV HGRILEMDIE EIQNCYYDKL RIYDGPSIHA 1930 1940 1950 1960 1970 1980 RLIGAYCGTQ TESFSSTGNS LTFHFYSDSS ISGKGFLLEW FAVDAPDGVL PTIAPGACGG 1990 2000 2010 2020 2030 2040 FLRTGDAPVF LFSPGWPDSY SNRVDCTWLI QAPDSTVELN ILSLDIESHR TCAYDSLVIR 2050 2060 2070 2080 2090 2100 DGDNNLAQQL AVLCGREIPG PIRSTGEYMF IRFTSDSSVT RAGFNASFHK SCGGYLHADR 2110 2120 2130 2140 2150 2160 GIITSPKYPE TYPSNLNCSW HVLVQSGLTI AVHFEQPFQI PNGDSSCNQG DYLVLRNGPD 2170 2180 2190 2200 2210 2220 ICSPPLGPPG GNGHFCGSHA SSTLFTSDNQ MFVQFISDHS NEGQGFKIKY EAKSLACGGN 2230 2240 2250 2260 2270 2280 VYIHDADSAG YVTSPNHPHN YPPHADCIWI LAAPPETRIQ LQFEDRFDIE VTPNCTSNYL 2290 2300 2310 2320 2330 2340 ELRDGVDSDA PILSKFCGTS LPSSQWSSGE VMYLRFRSDN SPTHVGFKAK YSIAQCGGRV 2350 2360 2370 2380 2390 2400 PGQSGVVESI GHPTLPYRDN LFCEWHLQGL SGHYLTISFE DFNLQNSSGC EKDFVEIWDN 2410 2420 2430 2440 2450 2460 HTSGNILGRY CGNTIPDSID TSSNTAVVRF VTDGSVTASG FRLRFESSME ECGGDLQGSI 2470 2480 2490 2500 2510 2520 GTFTSPNYPN PNPHGRICEW RITAPEGRRI TLMFNNLRLA THPSCNNEHV IVFNGIRSNS 2530 2540 2550 2560 2570 2580 PQLEKLCSSV NVSNEIKSSG NTMKVIFFTD GSRPYGGFTA SYTSSEDAVC GGSLPNTPEG 2590 2600 2610 2620 2630 2640 NFTSPGYDGV RNYSRNLNCE WTLSNPNQGN SSISIHFEDF YLESHQDCQF DVLEFRVGDA 2650 2660 2670 2680 2690 2700 DGPLMWRLCG PSKPTLPLVI PYSQVWIHFV TNERVEHIGF HAKYSFTDCG GIQIGDSGVI 2710 2720 2730 2740 2750 2760 TSPNYPNAYD SLTHCSSLLE APQGHTITLT FSDFDIEPHT TCAWDSVTVR NGGSPESPII 2770 2780 2790 2800 2810 2820 GQYCGNSNPR TIQSGSNQLV VTFNSDHSLQ GGGFYATWNT QTLGCGGIFH SDNGTIRSPH 2830 2840 2850 2860 2870 2880 WPQNFPENSR CSWTAITHKS KHLEISFDNN FLIPSGDGQC QNSFVKVWAG TEEVDKALLA 2890 2900 2910 2920 2930 2940 TGCGNVAPGP VITPSNTFTA VFQSQEAPAQ GFSASFVSRC GSNFTGPSGY IISPNYPKQY 2950 2960 2970 2980 2990 3000 DNNMNCTYVI EANPLSVVLL TFVSFHLEAR SAVTGSCVND GVHIIRGYSV MSTPFATVCG 3010 3020 3030 3040 3050 3060 DEMPAPLTIA GPVLLNFYSN EQITDFGFKF SYRIISCGGV FNFSSGIITS PAYSYADYPN 3070 3080 3090 3100 3110 3120 DMHCLYTITV SDDKVIELKF SDFDVVPSTS CSHDYLAIYD GANTSDPLLG KFCGSKRPPN 3130 3140 3150 3160 3170 3180 VKSSNNSMLL VFKTDSFQTA KGWKMSFRQT LGPQQGCGGY LTGSNNTFAS PDSDSNGMYD 3190 3200 3210 3220 3230 3240 KNLNCVWIII APVNKVIHLT FNTFALEAAS TRQRCLYDYV KLYDGDSENA NLAGTFCGST 3250 3260 3270 3280 3290 3300 VPAPFISSGN FLTVQFISDL TLEREGFNAT YTIMDMPCGG TYNATWTPQN ISSPNSSDPD 3310 3320 3330 3340 3350 3360 VPFSICTWVI DSPPHQQVKI TVWALQLTSQ DCTQNYLQLQ DSPQGHGNSR FQFCGRNASA 3370 3380 3390 3400 3410 3420 VPVFYSSMST AMVIFKSGVV NRNSRMSFTY QIADCNRDYH KAFGNLRSPG WPDNYDNDKD 3430 3440 3450 3460 3470 3480 CTVTLTAPQN HTISLFFHSL GIENSVECRN DFLEVRNGSN SNSPLLGKYC GTLLPNPVFS 3490 3500 3510 3520 3530 3540 QNNELYLRFK SDSVTSDRGY EIIWTSSPSG CGGTLYGDRG SFTSPGYPGT YPNNTYCEWV 3550 3560 3570 3580 3590 3600 LVAPAGRLVT INFYFISIDD PGDCVQNYLT LYDGPNASSP SSGPYCGGDT SIAPFVASSN 3610 3620 QVFIKFHADY ARRPSAFRLT WDS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region." Kozyraki R., Kristiansen M., Silahtaroglu A., Hansen C., Jacobsen C., Tommerup N., Verroust P.J., Moestrup S.K. Blood 91:3593-3600(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 36-41, FUNCTION, BINDING TO THE GIF-COBALAMIN COMPLEX, PROTEOLYTIC PROCESSING, VARIANTS SER-253; TYR-1545; ILE-1769; TYR-2162 AND TRP-2717.
[2]	NHLBI resequencing and genotyping service (RS&G) Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The intrinsic factor-vitamin B12 receptor, cubilin, is a high-affinity apolipoprotein A-I receptor facilitating endocytosis of high-density lipoprotein." Kozyraki R., Fyfe J., Kristiansen M., Gerdes C., Jacobsen C., Cui S., Christensen E.I., Aminoff M., de la Chapelle A., Krahe R., Verroust P.J., Moestrup S.K. Nat. Med. 5:656-661(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH APOA1, FUNCTION.
[5]	"Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3)." Nykjaer A., Fyfe J.C., Kozyraki R., Leheste J.-R., Jacobsen C., Nielsen M.S., Verroust P.J., Aminoff M., de la Chapelle A., Moestrup S.K., Ray R., Gliemann J., Willnow T.E., Christensen E.I. Proc. Natl. Acad. Sci. U.S.A. 98:13895-13900(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH GC, FUNCTION.
[6]	"Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia." Kozyraki R., Fyfe J., Verroust P.J., Jacobsen C., Dautry-Varsat A., Gburek J., Willnow T.E., Christensen E.I., Moestrup S.K. Proc. Natl. Acad. Sci. U.S.A. 98:12491-12496(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TF, FUNCTION.
[7]	"The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless." Fyfe J.C., Madsen M., Hoejrup P., Christensen E.I., Tanner S.M., de la Chapelle A., He Q., Moestrup S.K. Blood 103:1573-1579(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH AMN, GLYCOSYLATION, FUNCTION.
[8]	"Identification of the ligands of protein interaction domains through a functional approach." Caratu G., Allegra D., Bimonte M., Schiattarella G.G., D'Ambrosio C., Scaloni A., Napolitano M., Russo T., Zambrano N. Mol. Cell. Proteomics 6:333-345(2007) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN A COMPLEX WITH LRP1 AND PID1, INTERACTION WITH LRP1 AND PID1.
[9]	"Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes." Andersen C.B., Madsen M., Storm T., Moestrup S.K., Andersen G.R. Nature 464:445-448(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 932-1388 IN COMPLEX WITH GIF AND CALCIUM IONS, INTERACTION WITH GIF, IDENTIFICATION IN CUBAM COMPLEX, SUBUNIT, DISULFIDE BONDS, GLYCOSYLATION AT ASN-984; ASN-1092; ASN-1168; ASN-1217; ASN-1285; ASN-1307; ASN-1319 AND ASN-1332.
[10]	"Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1." Aminoff M., Carter J.E., Chadwick R.B., Johnson C., Graesbeck R., Abdelaal M.A., Broch H., Jenner L.B., Verroust P.J., Moestrup S.K., de la Chapelle A., Krahe R. Nat. Genet. 21:309-313(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT RH-MGA1 LEU-1297, VARIANTS ILE-124; SER-253; THR-389; HIS-1032; TYR-1545; SER-1559; ILE-1769; PHE-2153; ARG-2575; ARG-2691; ILE-2879; VAL-2984; GLY-3002; ILE-3422 AND LYS-3552.
[11]	"Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin." Kristiansen M., Aminoff M., Jacobsen C., de La Chapelle A., Krahe R., Verroust P.J., Moestrup S.K. Blood 96:405-409(2000) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF VARIANT RH-MGA1 LEU-1297.
[12]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] GLN-786; VAL-2252; VAL-2914 AND VAL-3189.
[13]	"Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma." Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., Davies H., Jones D., Lin M.L., Teague J., Bignell G., Butler A., Cho J., Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., Jia M. , Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., Mudie L., Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., Kahnoski R.J., Anema J., Tuveson D.A., Perez-Mancera P.A., Mustonen V., Fischer A., Adams D.J., Rust A., Chan-On W., Subimerb C., Dykema K., Furge K., Campbell P.J., Teh B.T., Stratton M.R., Futreal P.A. Nature 469:539-542(2011) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT GLY-3258.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF034611 mRNA. Translation: AAC82612.1.
EF444970 Genomic DNA. Translation: ACA05973.1.
EF444970 Genomic DNA. Translation: ACA05974.1.
AL596445 , AL365215, AC067747, AL731551 Genomic DNA. Translation: CAH72450.1.
AL365215 , AL596445, AC067747, AL731551 Genomic DNA. Translation: CAH73630.1.
AL731551 , AL365215, AL596445, AC067747 Genomic DNA. Translation: CAI40246.1.

IPI

IPI00160130.

PIR

T09456.

RefSeq

NP_001072.2. NM_001081.3.

UniGene

Hs.166206.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3KQ4	X-ray	3.30	B/D/F	932-1388	[»]

ProteinModelPortal

O60494.

SMR

O60494. Positions 932-1388.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-58583N.

IntAct

O60494. 1 interaction.

STRING

9606.ENSP00000367064.

PTM databases

PhosphoSite

O60494.

Proteomic databases

PaxDb

O60494.

PRIDE

O60494.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000377833; ENSP00000367064; ENSG00000107611.

GeneID

8029.

KEGG

hsa:8029.

UCSC

uc001ioo.3. human.

Organism-specific databases

CTD

8029.

GeneCards

GC10M016906.

H-InvDB

HIX0035313.
HIX0035577.

HGNC

HGNC:2548. CUBN.

MIM

261100. phenotype.
602997. gene.

neXtProt

NX_O60494.

Orphanet

35858. Grasbeck-Imerslund disease.

PharmGKB

PA27044.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG287752.

HOGENOM

HOG000049236.

HOVERGEN

HBG080357.

InParanoid

O60494.

KO

K14616.

OMA

SIQLTIH.

OrthoDB

EOG4J6RPX.

PhylomeDB

O60494.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.
REACT_15493. Steroid hormones.

Gene expression databases

ArrayExpress

O60494.

Bgee

O60494.

CleanEx

HS_CUBN.

Genevestigator

O60494.

GermOnline

ENSG00000107611. Homo sapiens.

Family and domain databases

Gene3D

2.60.120.290. 27 hits.

InterPro

IPR000859. CUB_dom.
IPR000742. EG-like_dom.
IPR001881. EGF-like_Ca-bd.
IPR013032. EGF-like_CS.
IPR000152. EGF-type_Asp/Asn_hydroxyl_site.
IPR018097. EGF_Ca-bd_CS.
IPR024731. EGF_dom_MSP1-like.
IPR009030. Growth_fac_rcpt.
[Graphical view]

Pfam

PF00431. CUB. 27 hits.
PF00008. EGF. 3 hits.
PF12947. EGF_3. 1 hit.
PF07645. EGF_CA. 3 hits.
[Graphical view]

SMART

SM00042. CUB. 27 hits.
SM00181. EGF. 5 hits.
SM00179. EGF_CA. 3 hits.
[Graphical view]

SUPFAM

SSF49854. CUB. 27 hits.
SSF57184. Grow_fac_recept. 1 hit.

PROSITE

PS00010. ASX_HYDROXYL. 4 hits.
PS01180. CUB. 27 hits.
PS00022. EGF_1. 4 hits.
PS01186. EGF_2. 2 hits.
PS50026. EGF_3. 6 hits.
PS01187. EGF_CA. 3 hits.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00115. Cyanocobalamin.
DB00200. Hydroxocobalamin.

EvolutionaryTrace

O60494.

GenomeRNAi

8029.

NextBio

30607.

SOURCE

Search...

Entry information

Entry name

CUBN_HUMAN

Accession

Primary (citable) accession number: O60494
Secondary accession number(s): B0YIZ4, Q5VTA6, Q96RU9

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 7, 2006
Last sequence update:	November 2, 2010
Last modified:	May 1, 2013
This is version 116 of the entry and version 5 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.