P08246 (ELNE_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Neutrophil elastase
EC=3.4.21.37

Alternative name(s):
Bone marrow serine protease
Elastase-2
Human leukocyte elastase
Short name=HLE
Medullasin
PMN elastase

Gene names

Name:	ELANE
Synonyms:	ELA2

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	267 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	Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis. Ref.15
Catalytic activity	Hydrolysis of proteins, including elastin. Preferential cleavage: Val-|-Xaa > Ala-|-Xaa.
Subunit structure	Interacts with NOTCH2NL. Ref.16
Tissue specificity	Bone marrow cells.
Involvement in disease	Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:162800]; also known as cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency. Ref.16 Ref.21 Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:202700]. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 109/l and early onset of severe bacterial infections. Ref.26
Sequence similarities	Belongs to the peptidase S1 family. Elastase subfamily. Contains 1 peptidase S1 domain.
Sequence caution	The sequence CAA29300.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Signal
Molecular function	Hydrolase Protease Serine protease
PTM	Disulfide bond Glycoprotein Zymogen
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	cellular calcium ion homeostasis Non-traceable author statement Ref.15. Source: UniProtKB negative regulation of chemokine biosynthetic process Inferred from direct assay. Source: UniProtKB negative regulation of chemotaxis Non-traceable author statement Ref.15. Source: UniProtKB negative regulation of inflammatory response Non-traceable author statement Ref.15. Source: UniProtKB negative regulation of interleukin-8 biosynthetic process Inferred from direct assay. Source: UniProtKB positive regulation of MAP kinase activity Non-traceable author statement. Source: UniProtKB positive regulation of interleukin-8 biosynthetic process Inferred from direct assay. Source: UniProtKB positive regulation of smooth muscle cell proliferation Inferred from direct assay. Source: UniProtKB protein catabolic process Non-traceable author statement. Source: UniProtKB proteolysis Inferred from direct assay. Source: MGI response to UV Inferred from direct assay. Source: UniProtKB
Cellular component	cell surface Inferred from direct assay. Source: UniProtKB extracellular region Non-traceable author statement. Source: UniProtKB secretory granule Inferred from direct assay. Source: MGI
Molecular function	bacterial cell surface binding Non-traceable author statement. Source: UniProtKB cytokine binding Inferred from physical interaction. Source: UniProtKB heparin binding Inferred from direct assay. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 27

27

Potential

Propeptide

28 – 29

2

PRO_0000027703

Chain

30 – 267

238

Neutrophil elastase

PRO_0000027704

Regions

Domain

30 – 247

218

Peptidase S1

Sites

Active site

70

1

Charge relay system

Active site

117

1

Charge relay system

Active site

202

1

Charge relay system

Amino acid modifications

Glycosylation

88

1

N-linked (GlcNAc...) Ref.17

Glycosylation

124

1

N-linked (GlcNAc...) Ref.8

Glycosylation

173

1

N-linked (GlcNAc...) Ref.8 Ref.17

Disulfide bond

55 ↔ 71

Ref.8

Disulfide bond

151 ↔ 208

Ref.8

Disulfide bond

181 ↔ 187

Ref.8

Disulfide bond

198 ↔ 223

Ref.8

Natural variations

Natural variant

25

1

A → V in SCN1. Ref.26

VAR_064512

Natural variant

32

1

G → V in CH. Ref.21

VAR_009538

Natural variant

55

1

C → Y in GFI1. Ref.23

VAR_038609

Natural variant

57

1

A → T in GFI1. Ref.22

VAR_038610

Natural variant

60

1

I → T in GFI1. Ref.22

VAR_038611

Natural variant

71

1

C → R in GFI1. Ref.24
Corresponds to variant rs28931611 [ dbSNP | Ensembl ].

VAR_038612

Natural variant

71

1

C → S in GFI1. Ref.22

VAR_038613

Natural variant

85

1

G → E in GFI1. Ref.23

VAR_038614

Natural variant

98

1

V → L in GFI1; located on the same allele as L-101; reduces proteolytic enzyme activity by slightly less than half; together with L-101 shows an additive effect with minimal remaining enzyme activity. Ref.25

VAR_038615

Natural variant

101

1

V → L in GFI1; located on the same allele as L-98; reduces proteolytic enzyme activity by slightly less than half; together with L-98 shows an additive effect with minimal remaining enzyme activity. Ref.25

VAR_038616

Natural variant

101

1

V → M in GFI1. Ref.22
Corresponds to variant rs28929494 [ dbSNP | Ensembl ].

VAR_038617

Natural variant

123

1

L → PQL in GFI1.

VAR_038618

Natural variant

126

1

S → L in GFI1. Ref.22 Ref.23

VAR_038619

Natural variant

139

1

P → L in GFI1. Ref.22
Corresponds to variant rs28929493 [ dbSNP | Ensembl ].

VAR_038620

Natural variant

151

1

C → S in GFI1. Ref.23

VAR_038621

Natural variant

166

1

A → T in SCN1; the patient also carries mutation Lys-116 in G6PC3. Ref.26

VAR_064513

Natural variant

177

1

V → F in CH. Ref.21

VAR_009539

Natural variant

190 – 199

10

Missing in GFI1.

VAR_038622

Natural variant

191

1

R → Q in CH; loss of interaction with NOTCH2NL and loss of NOTCH2NL and NOTCH2 proteolytic cleavage. Ref.16 Ref.21

VAR_009540

Natural variant

205

1

P → R in GFI1. Ref.23

VAR_038623

Natural variant

210

1

G → V in GFI1. Ref.22

VAR_038624

Natural variant

214

1

G → R in GFI1. Ref.22

VAR_038625

Natural variant

219

1

V → I. Ref.5
Corresponds to variant rs17216656 [ dbSNP | Ensembl ].

VAR_019237

Natural variant

257

1

P → L. Ref.5
Corresponds to variant rs17216663 [ dbSNP | Ensembl ].

VAR_019238

Natural variant

262

1

P → L. Ref.5
Corresponds to variant rs17216670 [ dbSNP | Ensembl ].

VAR_019239

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

267

Helix Strand Turn

Details...

Beta strand

44 – 49

6

Beta strand

52 – 61

10

Beta strand

64 – 67

4

Helix

69 – 71

3

Turn

72 – 74

3

Helix

77 – 79

3

Beta strand

81 – 85

5

Beta strand

97 – 99

3

Beta strand

101 – 106

6

Turn

111 – 114

4

Beta strand

119 – 125

7

Beta strand

130 – 132

3

Beta strand

150 – 156

7

Beta strand

158 – 160

3

Turn

161 – 163

3

Beta strand

170 – 176

7

Beta strand

185 – 189

5

Beta strand

205 – 208

4

Beta strand

211 – 222

12

Beta strand

226 – 228

3

Beta strand

230 – 234

5

Helix

235 – 238

4

Helix

239 – 246

8

Sequences

	Sequence		Length	Mass (Da)
	P08246 [UniParc]. Last modified August 1, 1988. Version 1. Checksum: 3F7610DC33CAA4B9	FASTA	267	28,518
	10 20 30 40 50 60 MTLGRRLACL FLACVLPALL LGGTALASEI VGGRRARPHA WPFMVSLQLR GGHFCGATLI 70 80 90 100 110 120 APNFVMSAAH CVANVNVRAV RVVLGAHNLS RREPTRQVFA VQRIFENGYD PVNLLNDIVI 130 140 150 160 170 180 LQLNGSATIN ANVQVAQLPA QGRRLGNGVQ CLAMGWGLLG RNRGIASVLQ ELNVTVVTSL 190 200 210 220 230 240 CRRSNVCTLV RGRQAGVCFG DSGSPLVCNG LIHGIASFVR GGCASGLYPD AFAPVAQFVN 250 260 WIDSIIQRSE DNPCPHPRDP DPASRTH

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Nucleotide sequence of human bone marrow serine protease (medullasin) gene." Nakamura H., Okano K., Aoki Y., Shimizu H., Naruto M. Nucleic Acids Res. 15:9601-9601(1987) [PubMed: 3479752] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Structure of the human neutrophil elastase gene." Takahashi H., Nukiwa T., Yoshimura K., Quick C.D., States D.J., Holmes M.D., Whang-Peng J., Knutsen T., Crystal R.G. J. Biol. Chem. 263:14739-14747(1988) [PubMed: 2902087] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"The human neutrophil elastase gene. Analysis of the nucleotide sequence reveals three distinct classes of repetitive DNA." Farley D., Travis J., Salvesen G. Biol. Chem. Hoppe-Seyler 370:737-744(1989) [PubMed: 2775493] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Functional expression of human leukocyte elastase (HLE)/medullasin in eukaryotic cells." Okano K., Aoki Y., Shimizu H., Naruto M. Biochem. Biophys. Res. Commun. 167:1326-1332(1990) [PubMed: 2322278] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	NIEHS SNPs program Submitted (APR-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ILE-219; LEU-257 AND LEU-262.
[6]	"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]. Tissue: Lung.
[7]	"Molecular cloning of complementary DNA for human medullasin: an inflammatory serine protease in bone marrow cells." Okano K., Aoki Y., Sakurai T., Kajitani M., Kanai S., Shimazu T., Shimizu H., Naruto M. J. Biochem. 102:13-16(1987) [PubMed: 2822677] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 30-267.
[8]	"Primary structure of human neutrophil elastase." Sinha S., Watorek W., Karr S., Giles J., Bode W., Travis J. Proc. Natl. Acad. Sci. U.S.A. 84:2228-2232(1987) [PubMed: 3550808] [Abstract] Cited for: PROTEIN SEQUENCE OF 30-247.
[9]	Travis J., Giles P.J., Porcelli L., Reilly C.F., Baugh R., Powers J. (In) Protein degradation in health and disease, Ciba Foundation Symposium, pp.75:51-68, Excerpta Medica, Amsterdam and Oxford (1980) Cited for: PRELIMINARY PROTEIN SEQUENCE OF 30-103.
[10]	"Antibiotic proteins of human polymorphonuclear leukocytes." Gabay J.E., Scott R.W., Campanelli D., Griffith J., Wilde C., Marra M.N., Seeger M., Nathan C.F. Proc. Natl. Acad. Sci. U.S.A. 86:5610-5614(1989) [PubMed: 2501794] [Abstract] Cited for: PROTEIN SEQUENCE OF 30-49.
[11]	"Use of proteinase 3 purified by reverse phase HPLC to detect autoantibodies in systemic vasculitis." Gaskin G., Kendal H., Coulthart A., Turner N., Pusey C.D. J. Immunol. Methods 180:25-33(1995) [PubMed: 7897245] [Abstract] Cited for: PROTEIN SEQUENCE OF 30-49. Tissue: Neutrophil.
[12]	"Myelomonocytic cell lineage expression of the neutrophil elastase gene." Takahashi H., Nukiwa T., Basset P., Cystal R.G. J. Biol. Chem. 263:2543-2547(1988) [PubMed: 3422232] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 75-267.
[13]	"Molecular cloning of human neutrophil elastase." Farley D., Salvesen G.S., Travis J. Biol. Chem. Hoppe-Seyler 369:3-7(1988) [PubMed: 2462434] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 123-267.
[14]	"The primary structure and elastinolytic activity of medullasin (a serine protease of bone marrow)." Aoki Y., Hase T. Biochem. Biophys. Res. Commun. 178:501-506(1991) [PubMed: 1859409] [Abstract] Cited for: PROTEIN SEQUENCE OF 262-267.
[15]	"Human leukocyte elastase and cathepsin G are specific inhibitors of C5a-dependent neutrophil enzyme release and chemotaxis." Tralau T., Meyer-Hoffert U., Schroder J.M., Wiedow O. Exp. Dermatol. 13:316-325(2004) [PubMed: 15140022] [Abstract] Cited for: FUNCTION.
[16]	"A novel notch protein, N2N, targeted by neutrophil elastase and implicated in hereditary neutropenia." Duan Z., Li F.-Q., Wechsler J., Meade-White K., Williams K., Benson K.F., Horwitz M. Mol. Cell. Biol. 24:58-70(2004) [PubMed: 14673143] [Abstract] Cited for: INTERACTION WITH NOTCH2NL, CHARACTERIZATION OF VARIANT CH GLN-191.
[17]	"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry." Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H. J. Proteome Res. 8:651-661(2009) [PubMed: 19159218] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-88 AND ASN-173, MASS SPECTROMETRY. Tissue: Liver.
[18]	"Structure of human neutrophil elastase in complex with a peptide chloromethyl ketone inhibitor at 1.84-A resolution." Navia M.A., McKeever B.M., Springer J.P., Lin T.-Y., Williams H.R., Fluder E.M., Dorn C.P., Hoogsteen K. Proc. Natl. Acad. Sci. U.S.A. 86:7-11(1989) [PubMed: 2911584] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.84 ANGSTROMS).
[19]	"The refined 2.3-A crystal structure of human leukocyte elastase in a complex with a valine chloromethyl ketone inhibitor." Wei A.-Z., Mayr I., Bode W. FEBS Lett. 234:367-373(1988) [PubMed: 3391280] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
[20]	"X-ray crystal structure of the complex of human leukocyte elastase (PMN elastase) and the third domain of the turkey ovomucoid inhibitor." Bode W., Wei A.-Z., Huber R., Meyer E., Travis J., Neumann S. EMBO J. 5:2453-2458(1986) [PubMed: 3640709] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS).
[21]	"Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis." Horwitz M., Benson K.F., Person R.E., Aprikyan A.G., Dale D.C. Nat. Genet. 23:433-436(1999) [PubMed: 10581030] [Abstract] Cited for: VARIANTS CH VAL-32; PHE-177 AND GLN-191.
[22]	"Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia." Dale D.C., Person R.E., Bolyard A.A., Aprikyan A.G., Bos C., Bonilla M.A., Boxer L.A., Kannourakis G., Zeidler C., Welte K., Benson K.F., Horwitz M. Blood 96:2317-2322(2000) [PubMed: 11001877] [Abstract] Cited for: VARIANTS GFI1 THR-57; THR-60; SER-71; MET-101; LEU-126; LEU-139; VAL-210 AND ARG-214.
[23]	"Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease." Ancliff P.J., Gale R.E., Liesner R., Hann I.M., Linch D.C. Blood 98:2645-2650(2001) [PubMed: 11675333] [Abstract] Cited for: VARIANTS GFI1 TYR-55; GLU-85; PRO-GLN-LEU-123 INS; LEU-126; SER-151; 190-VAL--PHE-199 DEL AND ARG-205.
[24]	"Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia." Ancliff P.J., Gale R.E., Watts M.J., Liesner R., Hann I.M., Strobel S., Linch D.C. Blood 100:707-709(2002) [PubMed: 12091371] [Abstract] Cited for: VARIANT GFI1 ARG-71.
[25]	"Double de novo mutations of ELA2 in cyclic and severe congenital neutropenia." Salipante S.J., Benson K.F., Luty J., Hadavi V., Kariminejad R., Kariminejad M.H., Rezaei N., Horwitz M.S. Hum. Mutat. 28:874-881(2007) [PubMed: 17436313] [Abstract] Cited for: VARIANTS GFI1 LEU-98 AND LEU-101, CHARACTERIZATION OF VARIANTS GFI1 LEU-98 AND LEU-101.
[26]	"Digenic mutations in severe congenital neutropenia." Germeshausen M., Zeidler C., Stuhrmann M., Lanciotti M., Ballmaier M., Welte K. Haematologica 95:1207-1210(2010) [PubMed: 20220065] [Abstract] Cited for: VARIANTS SCN1 VAL-25 AND THR-166.
+	Additional computationally mapped references.

Web resources

ELA2base

ELA2 mutation db

GeneReviews

NIEHS-SNPs

Wikipedia

Elastase entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

Y00477 Genomic DNA. Translation: CAA68537.1.
M20203 , M20199, M20200, M20201 Genomic DNA. Translation: AAA36359.1.
M34379 mRNA. Translation: AAA36173.1.
AY596461 Genomic DNA. Translation: AAS89303.1.
BC074816 mRNA. Translation: AAH74816.1.
BC074817 mRNA. Translation: AAH74817.1.
D00187 mRNA. Translation: BAA00128.1.
X05875 mRNA. Translation: CAA29299.1.
X05875 mRNA. Translation: CAA29300.1. Different initiation.
J03545 mRNA. Translation: AAA52378.1.
M27783 mRNA. Translation: AAA35792.1.

IPI

IPI00027769.

PIR

ELHUL. A31976.

RefSeq

NP_001963.1. NM_001972.2.

UniGene

Hs.99863.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1B0F	X-ray	3.00	A	30-247	[»]
1H1B	X-ray	2.00	A/B	30-247	[»]
1HNE	X-ray	1.84	E	30-247	[»]
1PPF	X-ray	1.80	E	30-247	[»]
1PPG	X-ray	2.30	E	30-247	[»]
2RG3	X-ray	1.80	A	30-247	[»]
2Z7F	X-ray	1.70	E	30-247	[»]
3Q76	X-ray	1.86	A/B	30-247	[»]
3Q77	X-ray	2.00	A	30-247	[»]

ProteinModelPortal

P08246.

SMR

P08246. Positions 30-247.

ModBase

Search...

Protein-protein interaction databases

IntAct

P08246. 1 interaction.

STRING

P08246.

Protein family/group databases

MEROPS

S01.131.

Polymorphism databases

DMDM

119292.

Proteomic databases

PeptideAtlas

P08246.

PRIDE

P08246.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000263621; ENSP00000263621; ENSG00000197561.

GeneID

1991.

KEGG

hsa:1991.

UCSC

uc002lqb.1. human.

Organism-specific databases

CTD

1991.

GeneCards

GC19P000852.

H-InvDB

HIX0040125.

HGNC

HGNC:3309. ELANE.

HPA

CAB015409.

MIM

130130. gene.
162800. phenotype.
202700. phenotype.

neXtProt

NX_P08246.

Orphanet

486. Autosomal dominant severe congenital neutropenia.
2686. Cyclic neutropenia.

PharmGKB

PA165393391.
PA27735.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG08661.

GeneTree

ENSGT00580000081367.

HOGENOM

HBG755338.

HOVERGEN

HBG013304.

InParanoid

P08246.

OMA

WINSIIR.

OrthoDB

EOG4XSKQQ.

PhylomeDB

P08246.

Enzyme and pathway databases

BRENDA

3.4.21.37. 2681.

Pathway_Interaction_DB

amb2_neutrophils_pathway. amb2 Integrin signaling.

Gene expression databases

ArrayExpress

P08246.

Bgee

P08246.

CleanEx

HS_ELA2.

Genevestigator

P08246.

GermOnline

ENSG00000197561. Homo sapiens.

Family and domain databases

InterPro

IPR009003. Pept_cys/ser_Trypsin-like.
IPR018114. Peptidase_S1/S6_AS.
IPR001254. Peptidase_S1_S6.
IPR001314. Peptidase_S1A.
[Graphical view]

KO

K01327.

Pfam

PF00089. Trypsin. 1 hit.
[Graphical view]

PRINTS

PR00722. CHYMOTRYPSIN.

SMART

SM00020. Tryp_SPc. 1 hit.
[Graphical view]

SUPFAM

SSF50494. Pept_Ser_Cys. 1 hit.

PROSITE

PS50240. TRYPSIN_DOM. 1 hit.
PS00134. TRYPSIN_HIS. 1 hit.
PS00135. TRYPSIN_SER. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00058. Alpha-1-proteinase inhibitor.
DB00099. Filgrastim.
DB00019. Pegfilgrastim.

NextBio

8051.

SOURCE

Search...

Entry information

Entry name

ELNE_HUMAN

Accession

Primary (citable) accession number: P08246
Secondary accession number(s): P09649, Q6B0D9, Q6LDP5

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1988
Last sequence update:	August 1, 1988
Last modified:	January 25, 2012
This is version 135 of the entry and version 1 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.