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O95967

- FBLN4_HUMAN

UniProt

O95967 - FBLN4_HUMAN

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Protein

EGF-containing fibulin-like extracellular matrix protein 2

Gene
EFEMP2, FBLN4, UNQ200/PRO226
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

GO - Molecular functioni

  1. calcium ion binding Source: InterPro
  2. extracellular matrix structural constituent Source: ProtInc
  3. protein binding Source: IntAct
  4. transmembrane signaling receptor activity Source: InterPro

GO - Biological processi

  1. blood coagulation Source: InterPro
  2. extracellular matrix organization Source: Reactome
Complete GO annotation...

Keywords - Ligandi

Calcium

Enzyme and pathway databases

ReactomeiREACT_150331. Molecules associated with elastic fibres.

Names & Taxonomyi

Protein namesi
Recommended name:
EGF-containing fibulin-like extracellular matrix protein 2
Alternative name(s):
Fibulin-4
Short name:
FIBL-4
Protein UPH1
Gene namesi
Name:EFEMP2
Synonyms:FBLN4
ORF Names:UNQ200/PRO226
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 11

Organism-specific databases

HGNCiHGNC:3219. EFEMP2.

Subcellular locationi

GO - Cellular componenti

  1. basement membrane Source: ProtInc
  2. extracellular region Source: Reactome
  3. extracellular vesicular exosome Source: UniProt
  4. membrane Source: InterPro
Complete GO annotation...

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Involvement in diseasei

Cutis laxa, autosomal recessive, 1B (ARCL1B) [MIM:614437]: A connective tissue disorder characterized by loose, hyperextensible skin with decreased resilience and elasticity leading to a premature aged appearance. Face, hands, feet, joints, and torso may be differentially affected. The clinical spectrum of autosomal recessive cutis laxa is highly heterogeneous with respect to organ involvement and severity. ARCL1B features include emphysema, lethal pulmonary artery occlusion, aortic aneurysm, cardiopulmonary insufficiency, birth fractures, arachnodactyly, and fragility of blood vessels.
Note: The disease is caused by mutations affecting the gene represented in this entry.3 Publications
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti57 – 571E → K in ARCL1B. 1 Publication
VAR_027019
Natural varianti267 – 2671C → Y in ARCL1B. 1 Publication
VAR_067069
Natural varianti279 – 2791R → C in ARCL1B. 1 Publication
VAR_067070

Keywords - Diseasei

Disease mutation

Organism-specific databases

MIMi614437. phenotype.
Orphaneti90349. Autosomal recessive cutis laxa type 1.
314718. Lethal arteriopathy syndrome due to Fibulin-4 deficiency.
PharmGKBiPA27653.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2525 Reviewed predictionAdd
BLAST
Chaini26 – 443418EGF-containing fibulin-like extracellular matrix protein 2PRO_0000007575Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi58 ↔ 1211 Publication
Disulfide bondi65 ↔ 801 Publication
Disulfide bondi71 ↔ 1091 Publication
Disulfide bondi127 ↔ 140 By similarity
Disulfide bondi134 ↔ 149 By similarity
Disulfide bondi151 ↔ 162 By similarity
Disulfide bondi168 ↔ 177 By similarity
Disulfide bondi173 ↔ 186 By similarity
Disulfide bondi188 ↔ 201 By similarity
Glycosylationi198 – 1981N-linked (GlcNAc...) Reviewed prediction
Disulfide bondi207 ↔ 217 By similarity
Disulfide bondi213 ↔ 226 By similarity
Disulfide bondi228 ↔ 241 By similarity
Disulfide bondi247 ↔ 258 By similarity
Disulfide bondi254 ↔ 267 By similarity
Disulfide bondi269 ↔ 281 By similarity
Disulfide bondi287 ↔ 300 By similarity
Disulfide bondi294 ↔ 309 By similarity
Disulfide bondi315 ↔ 327 By similarity
Glycosylationi394 – 3941N-linked (GlcNAc...) Reviewed prediction

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiO95967.
PRIDEiO95967.

PTM databases

PhosphoSiteiO95967.

Expressioni

Gene expression databases

ArrayExpressiO95967.
BgeeiO95967.
CleanExiHS_EFEMP2.
GenevestigatoriO95967.

Organism-specific databases

HPAiHPA023270.

Interactioni

Binary interactionsi

WithEntry#Exp.IntActNotes
ATN1P542593EBI-743414,EBI-945980
ELNP155025EBI-743414,EBI-1222108
FBLN5Q9UBX53EBI-743414,EBI-947897
FBN1P355553EBI-743414,EBI-2505934
Hoxa1P090223EBI-743414,EBI-3957603From a different organism.
LOXP283004EBI-743414,EBI-3893481
RHOXF2Q9BQY42EBI-743414,EBI-372094

Protein-protein interaction databases

BioGridi119026. 38 interactions.
DIPiDIP-34518N.
IntActiO95967. 44 interactions.
MINTiMINT-1439082.
STRINGi9606.ENSP00000309953.

Structurei

Secondary structure

1
443
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi68 – 736
Beta strandi78 – 825
Beta strandi113 – 1164

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2KL7NMR-A54-123[»]
ProteinModelPortaliO95967.
SMRiO95967. Positions 54-309.

Miscellaneous databases

EvolutionaryTraceiO95967.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini36 – 8146EGF-like 1; atypicalAdd
BLAST
Domaini123 – 16341EGF-like 2; calcium-binding Reviewed predictionAdd
BLAST
Domaini164 – 20239EGF-like 3; calcium-binding Reviewed predictionAdd
BLAST
Domaini203 – 24240EGF-like 4; calcium-binding Reviewed predictionAdd
BLAST
Domaini243 – 28240EGF-like 5; calcium-binding Reviewed predictionAdd
BLAST
Domaini283 – 32846EGF-like 6; calcium-binding Reviewed predictionAdd
BLAST

Sequence similaritiesi

Belongs to the fibulin family.
Contains 6 EGF-like domains.

Keywords - Domaini

EGF-like domain, Repeat, Signal

Phylogenomic databases

eggNOGiNOG254862.
HOGENOMiHOG000234337.
HOVERGENiHBG051560.
InParanoidiO95967.
OMAiQECHNLP.
PhylomeDBiO95967.
TreeFamiTF317514.

Family and domain databases

InterProiIPR026823. cEGF.
IPR026824. Efemp2.
IPR000742. EG-like_dom.
IPR001881. EGF-like_Ca-bd_dom.
IPR013032. EGF-like_CS.
IPR000152. EGF-type_Asp/Asn_hydroxyl_site.
IPR018097. EGF_Ca-bd_CS.
IPR009030. Growth_fac_rcpt_N_dom.
IPR001491. Thrombomodulin.
[Graphical view]
PANTHERiPTHR24048:SF2. PTHR24048:SF2. 1 hit.
PfamiPF12662. cEGF. 2 hits.
PF07645. EGF_CA. 3 hits.
[Graphical view]
PRINTSiPR00907. THRMBOMODULN.
SMARTiSM00181. EGF. 1 hit.
SM00179. EGF_CA. 4 hits.
[Graphical view]
SUPFAMiSSF57184. SSF57184. 2 hits.
PROSITEiPS00010. ASX_HYDROXYL. 4 hits.
PS01186. EGF_2. 4 hits.
PS50026. EGF_3. 4 hits.
PS01187. EGF_CA. 6 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

O95967-1 [UniParc]FASTAAdd to Basket

« Hide

MLPCASCLPG SLLLWALLLL LLGSASPQDS EEPDSYTECT DGYEWDPDSQ    50
HCRDVNECLT IPEACKGEMK CINHYGGYLC LPRSAAVIND LHGEGPPPPV 100
PPAQHPNPCP PGYEPDDQDS CVDVDECAQA LHDCRPSQDC HNLPGSYQCT 150
CPDGYRKIGP ECVDIDECRY RYCQHRCVNL PGSFRCQCEP GFQLGPNNRS 200
CVDVNECDMG APCEQRCFNS YGTFLCRCHQ GYELHRDGFS CSDIDECSYS 250
SYLCQYRCIN EPGRFSCHCP QGYQLLATRL CQDIDECESG AHQCSEAQTC 300
VNFHGGYRCV DTNRCVEPYI QVSENRCLCP ASNPLCREQP SSIVHRYMTI 350
TSERSVPADV FQIQATSVYP GAYNAFQIRA GNSQGDFYIR QINNVSAMLV 400
LARPVTGPRE YVLDLEMVTM NSLMSYRASS VLRLTVFVGA YTF 443
Length:443
Mass (Da):49,405
Last modified:March 20, 2007 - v3
Checksum:i9315CFBBAA0FD3A7
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti57 – 571E → K in ARCL1B. 1 Publication
VAR_027019
Natural varianti259 – 2591I → V.7 Publications
Corresponds to variant rs601314 [ dbSNP | Ensembl ].
VAR_027020
Natural varianti267 – 2671C → Y in ARCL1B. 1 Publication
VAR_067069
Natural varianti279 – 2791R → C in ARCL1B. 1 Publication
VAR_067070

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti5 – 51A → T in CAA10791. 1 Publication
Sequence conflicti44 – 518EWDPDSQH → TQTAN in AAC62108. 1 Publication
Sequence conflicti46 – 461D → G in BAF84768. 1 Publication
Sequence conflicti96 – 961P → L in BAG50843. 1 Publication
Sequence conflicti103 – 1119AQHPNPCPP → VNTQPLPT in AAC62108. 1 Publication
Sequence conflicti294 – 2941C → W in AAC62108. 1 Publication
Sequence conflicti354 – 3563RSV → AER in AAC62108. 1 Publication
Sequence conflicti355 – 3551S → R in AAF65188. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AJ132819 mRNA. Translation: CAA10791.2.
AF093119 mRNA. Translation: AAC62108.1.
AF109121 mRNA. Translation: AAF65188.1.
AK000980 mRNA. Translation: BAG50843.1.
AK292079 mRNA. Translation: BAF84768.1.
AY358899 mRNA. Translation: AAQ89258.1.
AK075453 mRNA. Translation: BAG52143.1.
AP001201 Genomic DNA. No translation available.
BC010456 mRNA. Translation: AAH10456.1.
CCDSiCCDS8116.1.
RefSeqiNP_058634.4. NM_016938.4.
UniGeneiHs.731454.

Genome annotation databases

EnsembliENST00000307998; ENSP00000309953; ENSG00000172638.
ENST00000531972; ENSP00000435295; ENSG00000172638.
GeneIDi30008.
KEGGihsa:30008.
UCSCiuc001ofy.4. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AJ132819 mRNA. Translation: CAA10791.2 .
AF093119 mRNA. Translation: AAC62108.1 .
AF109121 mRNA. Translation: AAF65188.1 .
AK000980 mRNA. Translation: BAG50843.1 .
AK292079 mRNA. Translation: BAF84768.1 .
AY358899 mRNA. Translation: AAQ89258.1 .
AK075453 mRNA. Translation: BAG52143.1 .
AP001201 Genomic DNA. No translation available.
BC010456 mRNA. Translation: AAH10456.1 .
CCDSi CCDS8116.1.
RefSeqi NP_058634.4. NM_016938.4.
UniGenei Hs.731454.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
2KL7 NMR - A 54-123 [» ]
ProteinModelPortali O95967.
SMRi O95967. Positions 54-309.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 119026. 38 interactions.
DIPi DIP-34518N.
IntActi O95967. 44 interactions.
MINTi MINT-1439082.
STRINGi 9606.ENSP00000309953.

PTM databases

PhosphoSitei O95967.

Proteomic databases

PaxDbi O95967.
PRIDEi O95967.

Protocols and materials databases

DNASUi 30008.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000307998 ; ENSP00000309953 ; ENSG00000172638 .
ENST00000531972 ; ENSP00000435295 ; ENSG00000172638 .
GeneIDi 30008.
KEGGi hsa:30008.
UCSCi uc001ofy.4. human.

Organism-specific databases

CTDi 30008.
GeneCardsi GC11M065633.
GeneReviewsi EFEMP2.
HGNCi HGNC:3219. EFEMP2.
HPAi HPA023270.
MIMi 604633. gene.
614437. phenotype.
neXtProti NX_O95967.
Orphaneti 90349. Autosomal recessive cutis laxa type 1.
314718. Lethal arteriopathy syndrome due to Fibulin-4 deficiency.
PharmGKBi PA27653.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG254862.
HOGENOMi HOG000234337.
HOVERGENi HBG051560.
InParanoidi O95967.
OMAi QECHNLP.
PhylomeDBi O95967.
TreeFami TF317514.

Enzyme and pathway databases

Reactomei REACT_150331. Molecules associated with elastic fibres.

Miscellaneous databases

EvolutionaryTracei O95967.
GeneWikii EFEMP2.
GenomeRNAii 30008.
NextBioi 52820.
PROi O95967.
SOURCEi Search...

Gene expression databases

ArrayExpressi O95967.
Bgeei O95967.
CleanExi HS_EFEMP2.
Genevestigatori O95967.

Family and domain databases

InterProi IPR026823. cEGF.
IPR026824. Efemp2.
IPR000742. EG-like_dom.
IPR001881. EGF-like_Ca-bd_dom.
IPR013032. EGF-like_CS.
IPR000152. EGF-type_Asp/Asn_hydroxyl_site.
IPR018097. EGF_Ca-bd_CS.
IPR009030. Growth_fac_rcpt_N_dom.
IPR001491. Thrombomodulin.
[Graphical view ]
PANTHERi PTHR24048:SF2. PTHR24048:SF2. 1 hit.
Pfami PF12662. cEGF. 2 hits.
PF07645. EGF_CA. 3 hits.
[Graphical view ]
PRINTSi PR00907. THRMBOMODULN.
SMARTi SM00181. EGF. 1 hit.
SM00179. EGF_CA. 4 hits.
[Graphical view ]
SUPFAMi SSF57184. SSF57184. 2 hits.
PROSITEi PS00010. ASX_HYDROXYL. 4 hits.
PS01186. EGF_2. 4 hits.
PS50026. EGF_3. 4 hits.
PS01187. EGF_CA. 6 hits.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Sequence, recombinant expression and tissue localization of two novel extracellular matrix proteins, fibulin-3 and fibulin-4."
    Giltay R., Timpl R., Kostka G.
    Matrix Biol. 18:469-480(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT VAL-259.
    Tissue: Melanoma.
  2. Zemel R., Shaul Y.
    Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT VAL-259.
  3. "Isolation of a paralog of the Doyne honeycomb retinal dystrophy gene from the multiple retinopathy critical region on 11q13."
    Katsanis N., Venable S., Smith J.R., Lupski J.R.
    Hum. Genet. 106:66-72(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT VAL-259.
  4. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
    Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
    , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
    Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT VAL-259.
    Tissue: Embryo and Synovium.
  5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT VAL-259.
  6. "Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries."
    Otsuki T., Ota T., Nishikawa T., Hayashi K., Suzuki Y., Yamamoto J., Wakamatsu A., Kimura K., Sakamoto K., Hatano N., Kawai Y., Ishii S., Saito K., Kojima S., Sugiyama T., Ono T., Okano K., Yoshikawa Y.
    , Aotsuka S., Sasaki N., Hattori A., Okumura K., Nagai K., Sugano S., Isogai T.
    DNA Res. 12:117-126(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT VAL-259.
    Tissue: Placenta.
  7. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  8. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT VAL-259.
    Tissue: Brain.
  9. "Solution NMR structure of the EGF-like 1 domain of human fibulin-4."
    Northeast structural genomics consortium (NESG)
    Submitted (JUL-2009) to the PDB data bank
    Cited for: STRUCTURE BY NMR OF 54-123, DISULFIDE BONDS.
  10. "Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome."
    Hucthagowder V., Sausgruber N., Kim K.H., Angle B., Marmorstein L.Y., Urban Z.
    Am. J. Hum. Genet. 78:1075-1080(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT ARCL1B LYS-57.
  11. "Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa."
    Dasouki M., Markova D., Garola R., Sasaki T., Charbonneau N.L., Sakai L.Y., Chu M.L.
    Am. J. Med. Genet. A 143:2635-2641(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT ARCL1B CYS-279.
  12. "Lethal cutis laxa with contractural arachnodactyly, overgrowth and soft tissue bleeding due to a novel homozygous fibulin-4 gene mutation."
    Hoyer J., Kraus C., Hammersen G., Geppert J.P., Rauch A.
    Clin. Genet. 76:276-281(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT ARCL1B TYR-267.

Entry informationi

Entry nameiFBLN4_HUMAN
AccessioniPrimary (citable) accession number: O95967
Secondary accession number(s): A8K7R4
, B3KM31, B3KQT1, O75967
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: March 20, 2007
Last modified: September 3, 2014
This is version 150 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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