Reviewed, UniProtKB/Swiss-Prot P03950 (ANGI_HUMAN)

Names and origin

Protein names

Recommended name:
    Angiogenin
    EC=3.1.27.-
Alternative name(s):
    Ribonuclease 5
      Short name=RNase 5

Gene names

Name:	ANG
Synonyms:	RNASE5

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	147 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	May function as a tRNA-specific ribonuclease that binds to actin on the surface of endothelial cells; once bound, angiogenin is endocytosed and translocated to the nucleus, thereby promoting the endothelial invasiveness necessary for blood vessel formation. Angiogenin induces vascularization of normal and malignant tissues. Abolishes protein synthesis by specifically hydrolyzing cellular tRNAs. Ref.6
Subcellular location	Secreted.
Tissue specificity	Expressed predominantly in the liver. Also detected in endothelial cells and spinal cord neurons. Ref.5 Ref.17
Developmental stage	Low level expression in the developing fetus, increased in the neonate, and maximal in the adult.
Involvement in disease	Defects in ANG are the cause of susceptibility to amyotrophic lateral sclerosis type 9 (ALS9) [MIM:611895]. ALS is a degenerative disorder of motor neurons in the cortex, brain stem and spinal cord. ALS is characterized by muscular weakness and atrophy. Ref.17 Ref.15 Ref.16 Ref.18 Ref.19 Ref.20
Sequence similarities	Belongs to the pancreatic ribonuclease family.
Caution	It is uncertain whether Met-1 or Met-3 is the initiator.

Ontologies

Keywords
Biological process	Angiogenesis Differentiation
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Disease	Amyotrophic lateral sclerosis Disease mutation Neurodegeneration
Domain	Signal
Molecular function	Developmental protein Endonuclease Hydrolase Nuclease Protein synthesis inhibitor
PTM	Disulfide bond Pyrrolidone carboxylic acid
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	actin filament polymerization Inferred from sequence or structural similarity. Source: UniProtKB activation of phospholipase A2 activity Inferred from mutant phenotype. Source: UniProtKB activation of phospholipase C activity Inferred from mutant phenotype. Source: UniProtKB activation of protein kinase B activity Inferred from mutant phenotype. Source: UniProtKB angiogenesis Inferred from mutant phenotype. Source: UniProtKB cell communication Non-traceable author statement. Source: UniProtKB cell death Inferred from electronic annotation. Source: UniProtKB-KW cell migration Inferred from mutant phenotype. Source: UniProtKB diacylglycerol biosynthetic process Inferred from direct assay. Source: UniProtKB homeostatic process Non-traceable author statement. Source: UniProtKB negative regulation of smooth muscle cell proliferation Inferred from direct assay. Source: UniProtKB negative regulation of translation Inferred from electronic annotation. Source: UniProtKB-KW oocyte maturation Non-traceable author statement. Source: UniProtKB ovarian follicle development Non-traceable author statement. Source: UniProtKB placenta development Non-traceable author statement. Source: UniProtKB positive regulation of endothelial cell proliferation Inferred from direct assay. Source: UniProtKB positive regulation of phosphorylation Inferred from direct assay. Source: UniProtKB positive regulation of protein secretion Inferred from direct assay. Source: UniProtKB rRNA transcription Inferred from mutant phenotype. Source: UniProtKB response to hormone stimulus Inferred from direct assay. Source: UniProtKB response to hypoxia Inferred from direct assay. Source: UniProtKB
Cellular component	angiogenin-PRI complex Inferred from physical interaction. Source: UniProtKB basal lamina Inferred from direct assay. Source: UniProtKB cell soma Inferred from sequence or structural similarity. Source: UniProtKB extracellular space Inferred from direct assay. Source: UniProtKB growth cone Inferred from sequence or structural similarity. Source: UniProtKB nucleolus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	DNA binding Inferred by curator. Source: UniProtKB actin binding Inferred from direct assay. Source: UniProtKB copper ion binding Inferred from direct assay. Source: UniProtKB heparin binding Inferred from direct assay. Source: UniProtKB pancreatic ribonuclease activity Inferred from electronic annotation. Source: InterPro peptide binding Inferred from direct assay. Source: UniProtKB rRNA binding Traceable author statement. Source: UniProtKB receptor binding Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ACTN2	P35609	3	EBI-525291,EBI-77797
FST	P19883	2	EBI-525291,EBI-1571188
FST	P19883-2	2	EBI-525291,EBI-1571208

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 24

24

Ref.4

Chain

25 – 147

123

Angiogenin Ref.4 Ref.1

PRO_0000030843

Regions

Region

64 – 68

5

Substrate binding

Sites

Active site

37

1

Proton acceptor

Active site

138

1

Proton donor

Amino acid modifications

Modified residue

25

1

Pyrrolidone carboxylic acid Ref.4

Disulfide bond

50 ↔ 105

Ref.4

Disulfide bond

63 ↔ 116

Ref.4

Disulfide bond

81 ↔ 131

Ref.4

Natural variations

Natural variant

12

1

F → S in ALS9. Ref.19

VAR_044145

Natural variant

20

1

P → S in ALS9. Ref.17 Ref.19

VAR_044146

Natural variant

36

1

Q → L in ALS9; reduced ribonucleolytic activity; low angiogenic activity; reduced mitogenic activity; wild type far-UV CD spectra. Ref.16 Ref.18

VAR_044147

Natural variant

41

1

K → E in ALS9; reduced ribonucleolytic activity. Ref.17 Ref.16 Ref.18

VAR_044148

Natural variant

41

1

K → I in ALS9; loss of angiogenic activity; reduced ribonucleolytic activity; retains nuclear translocation. Ref.17 Ref.16 Ref.18

VAR_044149

Natural variant

52

1

S → N in ALS9; loss of angiogenic activity; reduced ribonucleolytic activity; unable to translocate to the nucleus. Ref.17

VAR_044150

Natural variant

55

1

R → K in ALS9; marginally reduced ribonucleolytic activity; wild type far-UV CD spectra. Ref.16 Ref.18

VAR_044151

Natural variant

63

1

C → W in ALS9; reduced ribonucleolytic activity; low angiogenic activity; reduced mitogenic activity; reduced thermal stability. Ref.16 Ref.18

VAR_044152

Natural variant

64

1

K → I in ALS9; reduced ribonucleolytic activity; low angiogenic activity; reduced mitogenic activity; moderate reduction of thermal stability. Ref.15 Ref.16 Ref.18

VAR_044153

Natural variant

70

1

I → V in some ALS9 patients; pathogenicity uncertain; reduced ribonucleolytic activity; moderate reduction of thermal stability. Ref.16 Ref.18 Ref.19

VAR_044154

Natural variant

84

1

K → E: dbSNP rs17560. Ref.2

VAR_013148

Natural variant

136

1

P → L in ALS9; loss of angiogenic activity; reduced ribonucleolytic activity; unable to translocate to the nucleus. Ref.17

VAR_044155

Natural variant

137

1

V → I in ALS9. Ref.19

VAR_044156

Natural variant

138

1

H → R in ALS9. Ref.19

VAR_044157

Experimental info

Mutagenesis

140

1

D → H, S or A: 15- to 18-fold increase in RNase activity. Ref.11

Mutagenesis

141

1

Q → G: Over 18-fold increase in RNase activity. Ref.11

Mutagenesis

143 – 144

2

IF → AA: 3- to 5-fold increase in RNase activity.

Secondary structure

1

.

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147

Helix Strand Turn

Details...

Turn

26 – 28

3

Helix

29 – 37

9

Helix

47 – 57

11

Turn

60 – 63

4

Beta strand

65 – 70

6

Helix

74 – 80

7

Beta strand

82 – 85

4

Beta strand

90 – 95

6

Beta strand

100 – 107

8

Beta strand

112 – 115

4

Beta strand

118 – 125

8

Beta strand

128 – 139

12

Helix

142 – 144

3

Sequences

	Sequence		Length	Mass (Da)
	P03950-1 [UniParc]. Last modified October 23, 1986. Version 1. Checksum: 9C462DA3C8D39ACC	FASTA	147	16,550
	10 20 30 40 50 60 MVMGLGVLLL VFVLGLGLTP PTLAQDNSRY THFLTQHYDA KPQGRDDRYC ESIMRRRGLT 70 80 90 100 110 120 SPCKDINTFI HGNKRSIKAI CENKNGNPHR ENLRISKSSF QVTTCKLHGG SPWPPCQYRA 130 140 TAGFRNVVVA CENGLPVHLD QSIFRRP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Sequence of the cDNA and gene for angiogenin, a human angiogenesis factor." Kurachi K., Davie E.W., Strydom D.J., Riordan J.F., Vallee B.L. Biochemistry 24:5494-5499(1985) [PubMed: 2866795] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Diversifying selection of the tumor-growth promoter angiogenin in primate evolution." Zhang J., Rosenberg H.F. Mol. Biol. Evol. 19:438-445(2002) [PubMed: 11919285] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLU-84.
[3]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]	"Amino acid sequence of human tumor derived angiogenin." Strydom D.J., Fett J.W., Lobb R.R., Alderman E.M., Bethune J.L., Riordan J.F., Vallee B.L. Biochemistry 24:5486-5494(1985) [PubMed: 2866794] [Abstract] Cited for: PROTEIN SEQUENCE OF 25-147, DISULFIDE BONDS.
[5]	"Tissue distribution and developmental expression of the messenger RNA encoding angiogenin." Weiner H.L., Weiner L.H., Swain J.L. Science 237:280-282(1987) [PubMed: 2440105] [Abstract] Cited for: TISSUE SPECIFICITY.
[6]	"Angiogenin is a cytotoxic, tRNA-specific ribonuclease in the RNase A superfamily." Saxena S.K., Rybak S.M., Davey R.T. Jr., Youle R.J., Ackerman E.J. J. Biol. Chem. 267:21982-21986(1992) [PubMed: 1400510] [Abstract] Cited for: FUNCTION.
[7]	"Crystal structure of human angiogenin reveals the structural basis for its functional divergence from ribonuclease." Acharya K.R., Shapiro R., Allen S.C., Riordan J.F., Vallee B.L. Proc. Natl. Acad. Sci. U.S.A. 91:2915-2919(1994) [PubMed: 8159679] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
[8]	"Molecular recognition of human angiogenin by placental ribonuclease inhibitor -- an X-ray crystallographic study at 2.0-A resolution." Papageorgiou A.C., Shapiro R., Acharya K.R. EMBO J. 16:5162-5177(1997) [PubMed: 9311977] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF COMPLEX WITH INHIBITOR.
[9]	"Refined crystal structures of native human angiogenin and two active site variants: implications for the unique functional properties of an enzyme involved in neovascularisation during tumour growth." Leonidas D.D., Shapiro R., Allen S.C., Subbarao G.V., Veluraja K., Acharya K.R. J. Mol. Biol. 285:1209-1233(1999) [PubMed: 9918722] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
[10]	"Binding of phosphate and pyrophosphate ions at the active site of human angiogenin as revealed by X-ray crystallography." Leonidas D.D., Chavali G.B., Jardine A.M., Li S., Shapiro R., Acharya K.R. Protein Sci. 10:1669-1676(2001) [PubMed: 11468363] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF MUTANT GLY-141 IN COMPLEX WITH PHOSPHATE AND PYROPHOSPHATE.
[11]	"Crystallographic studies on the role of the C-terminal segment of human angiogenin in defining enzymatic potency." Leonidas D.D., Shapiro R., Subbarao G.V., Russo A., Acharya K.R. Biochemistry 41:2552-2562(2002) [PubMed: 11851402] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS), MUTAGENESIS OF ASP-140; GLN-141 AND 143-ILE-PHE-144.
[12]	"The crystal structure of human angiogenin in complex with an antitumor neutralizing antibody." Chavali G.B., Papageorgiou A.C., Olson K.A., Fett J.W., Hu G., Shapiro R., Acharya K.R. Structure 11:875-885(2003) [PubMed: 12842050] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
[13]	"Crystallographic studies on structural features that determine the enzymatic specificity and potency of human angiogenin: Thr44, Thr80, and residues 38-41." Holloway D.E., Chavali G.B., Hares M.C., Baker M.D., Subbarao G.V., Shapiro R., Acharya K.R. Biochemistry 43:1230-1241(2004) [PubMed: 14756559] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF MUTANTS ASP-68 AND ALA-104.
[14]	"Three-dimensional solution structure of human angiogenin determined by 1H,15N-NMR spectroscopy -- characterization of histidine protonation states and pKa values." Lequin O., Thuering H., Robin M., Lallemand J.-Y. Eur. J. Biochem. 250:712-726(1997) [PubMed: 9461294] [Abstract] Cited for: STRUCTURE BY NMR.
[15]	"A novel candidate region for ALS on chromosome 14q11.2." Greenway M.J., Alexander M.D., Ennis S., Traynor B.J., Corr B., Frost E., Green A., Hardiman O. Neurology 63:1936-1938(2004) [PubMed: 15557516] [Abstract] Cited for: VARIANT ALS9 ILE-64.
[16]	"ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis." Greenway M.J., Andersen P.M., Russ C., Ennis S., Cashman S., Donaghy C., Patterson V., Swingler R., Kieran D., Prehn J., Morrison K.E., Green A., Acharya K.R., Brown R.H. Jr., Hardiman O. Nat. Genet. 38:411-413(2006) [PubMed: 16501576] [Abstract] Cited for: VARIANTS ALS9 LEU-36; ILE-41; GLU-41; LYS-55; TRP-63 AND ILE-64, VARIANT VAL-70.
[17]	"Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis." Wu D., Yu W., Kishikawa H., Folkerth R.D., Iafrate A.J., Shen Y., Xin W., Sims K., Hu G.-F. Ann. Neurol. 62:609-617(2007) [PubMed: 17886298] [Abstract] Cited for: VARIANTS ALS9 SER-20; ILE-41; ASN-52 AND LEU-136, CHARACTERIZATION OF VARIANTS ALS9 ILE-41; ASN-52 AND LEU-136, TISSUE SPECIFICITY.
[18]	"Characterization of human angiogenin variants implicated in amyotrophic lateral sclerosis." Crabtree B., Thiyagarajan N., Prior S.H., Wilson P., Iyer S., Ferns T., Shapiro R., Brew K., Subramanian V., Acharya K.R. Biochemistry 46:11810-11818(2007) [PubMed: 17900154] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS ALS9 LEU-36; ILE-41; GLU-41; LYS-55; TRP-63 AND ILE-64, CHARACTERIZATION OF VARIANT VAL-70.
[19]	"Identification of new ANG gene mutations in a large cohort of Italian patients with amyotrophic lateral sclerosis." Gellera C., Colombrita C., Ticozzi N., Castellotti B., Bragato C., Ratti A., Taroni F., Silani V. Neurogenetics 9:33-40(2008) [PubMed: 18087731] [Abstract] Cited for: VARIANTS ALS9 SER-12; SER-20; ILE-137 AND ARG-138, VARIANT VAL-70.
[20]	"A novel angiogenin gene mutation in a sporadic patient with amyotrophic lateral sclerosis from southern Italy." Conforti F.L., Sprovieri T., Mazzei R., Ungaro C., La Bella V., Tessitore A., Patitucci A., Magariello A., Gabriele A.L., Tedeschi G., Simone I.L., Majorana G., Valentino P., Condino F., Bono F., Monsurro M.R., Muglia M., Quattrone A. Neuromuscul. Disord. 18:68-70(2008) [PubMed: 17703939] [Abstract] Cited for: INVOLVEMENT IN ALS9.
+	Additional computationally mapped references.

Web resources

R&D Systems' cytokine mini-reviews: Angiogenin

Functional Glycomics Gateway - Glycan Binding

Angiogenin

GeneReviews

Cross-references

Sequence databases

EMBLGenBankDDBJ

M11567 Genomic DNA. Translation: AAA51678.1.
AF449647 Genomic DNA. Translation: AAL67710.1.
AF449648 Genomic DNA. Translation: AAL67711.1.
AF449649 Genomic DNA. Translation: AAL67712.1.
AF449650 Genomic DNA. Translation: AAL67713.1.
AF449651 Genomic DNA. Translation: AAL67714.1.
BC054880 mRNA. Translation: AAH54880.1.

IPI

IPI00008554.

PIR

NRHUAG. A90498.

RefSeq

NP_001091046.1.
NP_001136.1.

UniGene

Hs.283749

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1A4Y	X-ray	2.00	B/E	25-147	[»]
1ANG	X-ray	2.40	A	25-147	[»]
1AWZ	NMR	-	A	25-147	[»]
1B1E	X-ray	2.00	A	25-147	[»]
1B1I	X-ray	1.80	A	26-147	[»]
1B1J	X-ray	2.00	A	25-147	[»]
1GV7	X-ray	2.10	A	26-145	[»]
1H0D	X-ray	2.00	C	26-147	[»]
1H52	X-ray	2.00	A	26-147	[»]
1H53	X-ray	2.00	A	26-147	[»]
1HBY	X-ray	2.00	A	26-147	[»]
1K58	X-ray	2.70	A	26-147	[»]
1K59	X-ray	1.80	A	26-147	[»]
1K5A	X-ray	2.33	A	25-147	[»]
1K5B	X-ray	1.80	A	26-144	[»]
1UN3	X-ray	1.70	A	26-147	[»]
1UN4	X-ray	2.10	A	26-147	[»]
1UN5	X-ray	2.60	A	25-147	[»]
2ANG	X-ray	2.00	A	25-147	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:6062N.

IntAct

P03950. 6 interactions.

Proteomic databases

PeptideAtlas

P03950.

PRIDE

P03950.

Genome annotation databases

Ensembl

ENSG00000214274. Homo sapiens. [Contig view]

GeneID

283.

KEGG

hsa:283.

Organism-specific databases

GeneCards

GC14P020223.

HGNC

HGNC:483. ANG.

MIM

105850. gene.
611895. phenotype.

Orphanet

803. Amyotrophic lateral sclerosis.

PharmGKB

PA24790.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P03950.

HOVERGEN

P03950.

OMA

P03950. QVTTCKL.

Gene expression databases

ArrayExpress

P03950.

Bgee

P03950.

CleanEx

HS_ANG.

GermOnline

ENSG00000181784. Homo sapiens.

Family and domain databases

InterPro

IPR001427. RNaseA.
[Graphical view]

Gene3D

G3DSA:3.10.130.10. RNaseA. 1 hit.

PANTHER

PTHR11437. RNaseA. 1 hit.

Pfam

PF00074. RnaseA. 1 hit.
[Graphical view]

PRINTS

PR00794. RIBONUCLEASE.

ProDom

PD000535. RNaseA. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00092. RNAse_Pc. 1 hit.
[Graphical view]

PROSITE

PS00127. RNASE_PANCREATIC. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

1141.

SOURCE

Search...

Entry information

Entry name

ANGI_HUMAN

Accession

Primary (citable) accession number: P03950
Secondary accession number(s): Q8WXE7

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 23, 1986
Last sequence update:	October 23, 1986
Last modified:	June 16, 2009
This is version 121 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)