P13236 (CCL4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
C-C motif chemokine 4

Alternative name(s):
G-26 T-lymphocyte-secreted protein
HC21
Lymphocyte activation gene 1 protein
Short name=LAG-1
MIP-1-beta(1-69)
Macrophage inflammatory protein 1-beta
Short name=MIP-1-beta
PAT 744
Protein H400
SIS-gamma
Small-inducible cytokine A4
T-cell activation protein 2
Short name=ACT-2

Cleaved into the following chain:

1. MIP-1-beta(3-69)

Gene names

Name:	CCL4
Synonyms:	LAG1, MIP1B, SCYA4

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	92 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	Monokine with inflammatory and chemokinetic properties. Binds to CCR5. One of the major HIV-suppressive factors produced by CD8+ T-cells. Recombinant MIP-1-beta induces a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV). The processed form MIP-1-beta(3-69) retains the abilities to induce down-modulation of surface expression of the chemokine receptor CCR5 and to inhibit the CCR5-mediated entry of HIV-1 in T-cells. MIP-1-beta(3-69) is also a ligand for CCR1 and CCR2 isoform B. Ref.13 Ref.14 Ref.15
Subunit structure	Homodimer and heterodimer of MIP-1-alpha(4-69) and MIP-1-beta(3-69). Ref.15
Subcellular location	Secreted.
Induction	By mitogens.
Post-translational modification	N-terminal processed form MIP-1-beta(3-69) is produced by proteolytic cleavage after secretion from peripheral blood lymphocytes.
Sequence similarities	Belongs to the intercrine beta (chemokine CC) family.
Caution	Was originally (Ref.12) thought to be a ligand for CCR8.

Ontologies

Keywords
Biological process	Chemotaxis Inflammatory response
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Domain	Signal
Molecular function	Cytokine
PTM	Disulfide bond
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cell adhesion Traceable author statement PubMed 10929056. Source: ProtInc cell-cell signaling Traceable author statement Ref.2. Source: ProtInc cellular component movement Traceable author statement PubMed 9759849. Source: ProtInc chemotaxis Inferred from electronic annotation. Source: UniProtKB-KW establishment or maintenance of cell polarity Traceable author statement PubMed 9759849. Source: ProtInc immune response Traceable author statement PubMed 10929056. Source: ProtInc inflammatory response Traceable author statement Ref.2. Source: ProtInc negative regulation by host of viral transcription Inferred from direct assay PubMed 10841574. Source: UniProtKB positive regulation of calcium ion transport Inferred from direct assay PubMed 8699119. Source: UniProtKB positive regulation of calcium-mediated signaling Inferred from mutant phenotype PubMed 10679098. Source: UniProtKB positive regulation of natural killer cell chemotaxis Inferred from direct assay PubMed 7545673. Source: UniProtKB response to toxin Inferred from direct assay PubMed 10841574. Source: UniProtKB response to virus Traceable author statement PubMed 9743377. Source: ProtInc signal transduction Traceable author statement PubMed 10929056PubMed 9558100. Source: ProtInc
Cellular_component	extracellular space Traceable author statement Ref.2. Source: ProtInc
Molecular_function	chemokine activity Traceable author statement PubMed 10929056. 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

Chain

24 – 92

69

C-C motif chemokine 4

PRO_0000005164

Chain

26 – 92

67

MIP-1-beta(3-69)

PRO_0000005165

Amino acid modifications

Disulfide bond

34 ↔ 58

By similarity

Disulfide bond

35 ↔ 74

By similarity

Natural variations

Natural variant

12

1

M → V.
Corresponds to variant rs9635771 [ dbSNP | Ensembl ].

VAR_048702

Natural variant

20

1

P → L.
Corresponds to variant rs1130750 [ dbSNP | Ensembl ].

VAR_048703

Natural variant

80

1

S → T. Ref.10 Ref.11
Corresponds to variant rs1719152 [ dbSNP | Ensembl ].

VAR_059211

Experimental info

Sequence conflict

6

1

T → C in AAA36752. Ref.11

Sequence conflict

15

1

A → S in AAB00790. Ref.6

Sequence conflict

40 – 45

6

ARKLPR → REASS in AAA36656. Ref.3

Sequence conflict

56

1

S → I in AAA36752. Ref.11

Sequence conflict

70

1

S → G in CAA37722. Ref.6

Sequence conflict

70

1

S → G in AAB00790. Ref.6

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

92

Helix Strand Turn

Details...

Beta strand

26 – 28

3

Turn

30 – 32

3

Helix

45 – 47

3

Beta strand

48 – 53

6

Beta strand

58 – 60

3

Beta strand

63 – 67

5

Beta strand

68 – 70

3

Beta strand

72 – 75

4

Helix

80 – 90

11

Sequences

	Sequence		Length	Mass (Da)
	P13236 [UniParc]. Last modified January 1, 1990. Version 1. Checksum: F2EA7CF341B0E258	FASTA	92	10,212
	10 20 30 40 50 60 MKLCVTVLSL LMLVAAFCSP ALSAPMGSDP PTACCFSYTA RKLPRNFVVD YYETSSLCSQ 70 80 90 PAVVFQTKRS KQVCADPSES WVQEYVYDLE LN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification, cloning, and characterization of an immune activation gene." Lipes M.A., Napolitano M., Jeang K.-T., Chang N.T., Leonard W.J. Proc. Natl. Acad. Sci. U.S.A. 85:9704-9708(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Mitogenic activation of human T cells induces two closely related genes which share structural similarities with a new family of secreted factors." Zipfel P.F., Balke J., Irving S.G., Kelly K., Siebenlist U. J. Immunol. 142:1582-1590(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"A family of small inducible proteins secreted by leukocytes are members of a new superfamily that includes leukocyte and fibroblast-derived inflammatory agents, growth factors, and indicators of various activation processes." Brown K.D., Zurawski S.M., Mosmann T.R., Zurawski G. J. Immunol. 142:679-687(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: T-cell.
[4]	"Cloning and expression of a lymphocyte activation gene (LAG-1)." Baixeras E., Roman-Roman S., Jitsukawa S., Genevee C., Mechiche S., Viegas-Pequignot E., Hercend T., Triebel F. Mol. Immunol. 27:1091-1102(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. Tissue: Natural killer cell.
[5]	"Isolation and characterization of a cDNA encoding a putative cytokine which is induced by stimulation via the CD2 structure on human T lymphocytes." Chang H.C., Reinherz E.L. Eur. J. Immunol. 19:1045-1051(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: T-cell.
[6]	"The gene encoding the Act-2 cytokine. Genomic structure, HTLV-I/Tax responsiveness of 5' upstream sequences, and chromosomal localization." Napolitano M., Modi W.S., Cevario S.J., Gnarra J.R., Seuanez H.N., Leonard W.J. J. Biol. Chem. 266:17531-17536(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[7]	"Multiple products derived from two CCL4 loci: high incidence of a new polymorphism in HIV+ patients." Colobran R., Adreani P., Ashhab Y., Llano A., Este J.A., Dominguez O., Pujol-Borrell R., Juan M. J. Immunol. 174:5655-5664(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[8]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y., LaBaer J. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[9]	"DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage." Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., Chang J.L. , Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C. Nature 440:1045-1049(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[10]	"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 THR-80.
[11]	"A novel polypeptide secreted by activated human T lymphocytes." Miller M.D., Hata S., Waal Malefyt R., Krangel M.S. J. Immunol. 143:2907-2916(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 6-92, VARIANT THR-80. Tissue: T-cell.
[12]	"Identification of the CC chemokines TARC and macrophage inflammatory protein-1 beta as novel functional ligands for the CCR8 receptor." Bernardini G., Hedrick J., Sozzani S., Luini W., Spinetti G., Weiss M., Menon S., Zlotnik A., Mantovani A., Santoni A., Napolitano M. Eur. J. Immunol. 28:582-588(1998) [PubMed] [Europe PMC] [Abstract] Cited for: RECEPTOR INTERACTION.
[13]	"Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells." Cocchi F., DeVico A.L., Garzino-Demo A., Arya S.K., Gallo R.C., Lusso P. Science 270:1811-1815(1995) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[14]	"The assignment of chemokine-chemokine receptor pairs: TARC and MIP-1 beta are not ligands for human CC-chemokine receptor 8." Garlisi C.G., Xiao H., Tian F., Hedrick J.A., Billah M.M., Egan R.W., Umland S.P. Eur. J. Immunol. 29:3210-3215(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[15]	"Natural truncation of the chemokine MIP-1beta/CCL4 affects receptor specificity but not anti-HIV-1 activity." Guan E., Wang J., Roderiquez G., Norcross M.A. J. Biol. Chem. 277:32348-32352(2002) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION OF MIP-1-BETA(3-69) BY MASS SPECTROMETRY, FUNCTION, SUBUNIT.
[16]	"Macrophage inflammatory protein-1." Menten P., Wuyts A., Van Damme J. Cytokine Growth Factor Rev. 13:455-481(2002) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[17]	"High-resolution solution structure of the beta chemokine hMIP-1 beta by multidimensional NMR." Lodi P.J., Garrett D.S., Kuscewski J., Tsang M.L.S., Weatherbee J.A., Leonard W.J., Gronenborn A.M., Clore G.M. Science 263:1762-1767(1994) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR.
+	Additional computationally mapped references.

Web resources

Wikipedia

Macrophage inflammatory protein entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

J04130 mRNA. Translation: AAA51576.1.
M25316 mRNA. Translation: AAA57256.1.
M23502 mRNA. Translation: AAA36656.1.
X53683 mRNA. Translation: CAA37723.1.
X53682 Genomic DNA. Translation: CAA37722.2. Sequence problems.
X16166 mRNA. Translation: CAA34291.1.
M69203, M69201, M69202 Genomic DNA. Translation: AAB00790.1.
AY766446 mRNA. Translation: AAX07305.1.
AY766459 Genomic DNA. Translation: AAX07292.1.
CR542119 mRNA. Translation: CAG46916.1.
AC003976 Genomic DNA. No translation available.
BC104226 mRNA. Translation: AAI04227.1.
BC104227 mRNA. Translation: AAI04228.1.
BC107433 mRNA. Translation: AAI07434.1.
M57503 mRNA. Translation: AAA36752.1.

IPI

IPI00873565.

PIR

A31767. JH0319.

RefSeq

NP_001001435.1. NM_001001435.2.
NP_002975.1. NM_002984.2.
NP_996890.1. NM_207007.2.
XP_003960723.1. XM_003960674.1.

UniGene

Hs.655293.
Hs.661942.
Hs.75703.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1HUM	NMR	-	A/B	24-92	[»]
1HUN	NMR	-	A/B	24-92	[»]
1JE4	NMR	-	A	24-92	[»]
2FFK	NMR	-	B	24-92	[»]
2FIN	NMR	-	B	24-92	[»]
2X6L	X-ray	2.60	A/B/C/D/E	24-92	[»]
3TN2	X-ray	1.60	A	24-91	[»]

ProteinModelPortal

P13236.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-5840N.

IntAct

P13236. 2 interactions.

STRING

9606.ENSP00000250151.

Polymorphism databases

DMDM

127080.

Proteomic databases

PaxDb

P13236.

PeptideAtlas

P13236.

PRIDE

P13236.

Protocols and materials databases

DNASU

388372.
9560.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000250151; ENSP00000250151; ENSG00000129277.

GeneID

101060278.
388372.
6351.
9560.

KEGG

hsa:101060278.
hsa:388372.
hsa:6351.
hsa:9560.

UCSC

uc002hkw.1. human.

Organism-specific databases

CTD

388372.
6351.
9560.

GeneCards

GC17P034431.

HGNC

HGNC:10630. CCL4.

HPA

CAB007805.

MIM

182284. gene.

neXtProt

NX_P13236.

PharmGKB

PA35563.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG124416.

HOGENOM

HOG000036685.

HOVERGEN

HBG017871.

KO

K12964.

OMA

CANPAEE.

OrthoDB

EOG42Z4RR.

Enzyme and pathway databases

Pathway_Interaction_DB

il12_2pathway. IL12-mediated signaling events.

Reactome

REACT_111102. Signal Transduction.

Gene expression databases

ArrayExpress

P13236.

Bgee

P13236.

CleanEx

HS_CCL4.

Genevestigator

P13236.

GermOnline

ENSG00000129277. Homo sapiens.

Family and domain databases

InterPro

IPR000827. Chemokine_CC_CS.
IPR001811. Chemokine_IL8-like_dom.
[Graphical view]

Pfam

PF00048. IL8. 1 hit.
[Graphical view]

SMART

SM00199. SCY. 1 hit.
[Graphical view]

SUPFAM

SSF54117. Chemokine_IL8. 1 hit.

PROSITE

PS00472. SMALL_CYTOKINES_CC. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

CCL4. human.

EvolutionaryTrace

P13236.

NextBio

102005.

SOURCE

Search...

Entry information

Entry name

CCL4_HUMAN

Accession

Primary (citable) accession number: P13236
Secondary accession number(s): P22617 , Q13704, Q3SXL8, Q6FGI8

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 1, 1990
Last sequence update:	January 1, 1990
Last modified:	May 1, 2013
This is version 142 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.