Reviewed, UniProtKB/Swiss-Prot P51681 (CCR5_HUMAN)

Names and origin

Protein names

Recommended name:
    C-C chemokine receptor type 5
      Short name=C-C CKR-5
      Short name=CC-CKR-5
      Short name=CCR-5
      Short name=CCR5
Alternative name(s):
    HIV-1 fusion coreceptor
    CHEMR13
    CD_antigen=CD195

Gene names

Name:	CCR5
Synonyms:	CMKBR5

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	352 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Receptor for a number of inflammatory CC-chemokines including MIP-1-alpha, MIP-1-beta and RANTES and subsequently transduces a signal by increasing the intracellular calcium ion level. May play a role in the control of granulocytic lineage proliferation or differentiation. Acts as a coreceptor (CD4 being the primary receptor) for HIV-1 R5 isolates.
Subunit structure	Interacts with PRAF2. Interacts with HIV-1 surface protein gp120. Efficient ligand binding to CCL3/MIP-1alpha and CCR4/MIP-1beta requires sulfation, O-glycosylation and sialic acid modifications. Glycosylation on Ser-6 is required for efficient binding of CCL4. Interacts with ADRBK1.
Subcellular location	Cell membrane; Multi-pass membrane protein.
Tissue specificity	Highly expressed in spleen, thymus, in the myeloid cell line THP-1, in the promyeloblastic cell line KG-1A and on CD4+ and CD8+ T-cells. Medium levels in peripheral blood leukocytes and in small intestine. Low levels in ovary and lung.
Post-translational modification	Sulfated on at least 2 of the N-terminal tyrosines. Sulfation contributes to the efficiency of HIV-1 entry and is required for efficient binding of the chemokines, CCL3 and CCL4. O-glycosylated, but not N-glycosylated. Ser-6 appears to be the major site. Also sialylated glycans present which contribute to chemokine binding. Thr-16 and Ser-17 may also be glycosylated and, if so, with small moieties such as a T-antigen. Palmitoylation in the C-terminal is important for cell surface expression, and to a lesser extent, for HIV entry. Phosphorylation on serine residues in the C-terminal is stimulated by binding CC chemokines especially by APO-RANTES.
Polymorphism	Variations in CCR5 are associated with resistance or susceptibility to immunodeficiency virus type 1 (resistance or susceptibility to HIV-1) [MIM:609423]. Variations in CCR5 gene also influence the rate of progression to AIDS after infection. Ser-60 variant, a naturally occurring mutation in a conserved residue in the first intracellular domain of CCR5, results in reduced amounts of the protein in the membrane and consequently may be associated with reduced susceptibility to infection by microbes that depend on these molecules as their receptors. Variations in CCR5 are associated with susceptibility to West Nile virus (WNV) infection [MIM:610379].
Sequence similarities	Belongs to the G-protein coupled receptor 1 family.

Ontologies

Keywords
Biological process	Host-virus interaction
Cellular component	Cell membrane Membrane
Coding sequence diversity	Polymorphism
Domain	Transmembrane
Molecular function	G-protein coupled receptor Receptor Transducer
PTM	Glycoprotein Lipoprotein Palmitate Phosphoprotein Sulfation
Technical term	3D-structure
Gene Ontology (GO)
Biological process	G-protein coupled receptor protein signaling pathway Traceable author statement. Source: ProtInc cell-cell signaling Traceable author statement. Source: ProtInc cellular defense response Traceable author statement. Source: ProtInc chemotaxis Traceable author statement. Source: ProtInc elevation of cytosolic calcium ion concentration Traceable author statement. Source: ProtInc immune response Ref.1 Traceable author statement. Source: ProtInc inflammatory response Ref.1 Traceable author statement. Source: ProtInc initiation of viral infection Inferred from Experiment. Source: Reactome
Cellular component	endosome Traceable author statement. Source: ProtInc integral to plasma membrane Traceable author statement. Source: ProtInc
Molecular function	C-C chemokine receptor activity Ref.1 Non-traceable author statement. Source: UniProtKB actin binding Inferred from direct assay. Source: UniProtKB coreceptor activity Traceable author statement. Source: ProtInc phosphoinositide phospholipase C activity Ref.2 Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
MYH9	P35579	1	EBI-489374,EBI-350338

Sequence annotation (Features)

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	Feature key	Position(s)	Length	Description	Graphical view
Molecule processing
	Chain	1 – 352	352	C-C chemokine receptor type 5
Regions
	Topological domain	1 – 30	30	Extracellular Potential
	Transmembrane	31 – 58	28	1 Potential
	Topological domain	59 – 68	10	Cytoplasmic Potential
	Transmembrane	69 – 89	21	2 Potential
	Topological domain	90 – 102	13	Extracellular Potential
	Transmembrane	103 – 124	22	3 Potential
	Topological domain	125 – 141	17	Cytoplasmic Potential
	Transmembrane	142 – 166	25	4 Potential
	Topological domain	167 – 198	32	Extracellular Potential
	Transmembrane	199 – 218	20	5 Potential
	Topological domain	219 – 235	17	Cytoplasmic Potential
	Transmembrane	236 – 260	25	6 Potential
	Topological domain	261 – 277	17	Extracellular Potential
	Transmembrane	278 – 301	24	7 Potential
	Topological domain	302 – 352	51	Cytoplasmic Potential
Amino acid modifications
	Modified residue	3	1	Sulfotyrosine
	Modified residue	10	1	Sulfotyrosine Potential
	Modified residue	14	1	Sulfotyrosine Potential
	Modified residue	15	1	Sulfotyrosine Potential
	Modified residue	336	1	Phosphoserine; by BARK1
	Modified residue	337	1	Phosphoserine; by BARK1
	Modified residue	342	1	Phosphoserine; by BARK1
	Modified residue	349	1	Phosphoserine; by BARK1
	Lipidation	321	1	S-palmitoyl cysteine
	Lipidation	323	1	S-palmitoyl cysteine
	Lipidation	324	1	S-palmitoyl cysteine
	Glycosylation	6	1	O-linked (GalNAc...)
	Glycosylation	7	1	O-linked (GalNAc...) Probable
	Glycosylation	16	1	O-linked (GalNAc...) Potential
	Glycosylation	17	1	O-linked (GalNAc...) Potential
	Disulfide bond	101 ↔ 178		By similarity
Natural variations
	Natural variant	10	1	Y → D in INCCR5-71A) (No sulfation and greatly decreased binding CCL4 and CCL5; when associated with D-3; D-10 and D-15. Restored most CCL4 binding; when associated with D-3 and D-15.
	Natural variant	12	1	I → L
	Natural variant	20	1	C → S
	Natural variant	29	1	A → S: dbSNP rs1800939.
	Natural variant	31	1	R → H in INCCR5-72A.
	Natural variant	34	1	P → L in TZCCR5-179.
	Natural variant	42	1	I → F
	Natural variant	55	1	L → Q: dbSNP rs1799863.
	Natural variant	60	1	R → S Associated with susceptibility to HIV-1; reduced surface expression and function of CCR5 protein. dbSNP rs1800940.
	Natural variant	62	1	K → R in UGCCR5-145B.
	Natural variant	68	1	Y → H in ZWCCR5-7.
	Natural variant	73	1	A → V
	Natural variant	95	1	D → N in MWCCR5-107.
	Natural variant	97	1	G → E in INCCR5-467.
	Natural variant	122	1	L → P in ZWCCR5-7.
	Natural variant	158	1	F → S in UGCCR5-145A.
	Natural variant	176	1	Y → C in KECCR5-116.
	Natural variant	177	1	T → A in INCCR5-45C.
	Natural variant	178	1	C → R Found in a HIV-resistant individiual.
	Natural variant	185	1	S → N in UGCCR5-145A.
	Natural variant	210	1	M → V in ZWCCR5-7.
	Natural variant	214	1	Y → C in KECCR5-3B.
	Natural variant	215	1	S → L
	Natural variant	223	1	R → Q: dbSNP rs1800452.
	Natural variant	228	1	Missing
	Natural variant	239	1	T → S in INCCR5-71A.
	Natural variant	246	1	L → P in UGCCR5-145A.
	Natural variant	288	1	T → M in INCCR5-72A.
	Natural variant	301	1	G → V: dbSNP rs1800943.
	Natural variant	302	1	E → G in TZCCR5-179.
	Natural variant	303	1	K → E in THCCR5-5.
	Natural variant	306	1	N → S in MWCCR5-1567.
	Natural variant	322	1	K → R in THCCR5-5.
	Natural variant	333	1	E → G in THCCR5-2.
	Natural variant	335	1	A → V in MWCCR5-1567, MWCCR5-1568, ZWCCR5-14 and ZWCCR5-112. dbSNP rs1800944.
	Natural variant	339	1	Y → F in TZCCR5-181A and MWCCR5-107. dbSNP rs1800945.
	Natural variant	345	1	E → G in UGCCR5-145C.
Experimental info
	Mutagenesis	3	1	Y → D: No sulfation and greatly decreased binding CCL4 and CCL5; when associated with D-10; D-14 and D-15. Restored most CCL4 binding; when associated with D-10 and D-15
	Mutagenesis	3	1	Y → F: No sulfation and greatly decreases binding of CCL4 and CCL5; when associated with F-10; F-14 and F-15
	Mutagenesis	6	1	S → A: No change in glycosylation status and greatly decreased CCL4 binding. Loss of molecular mass of about 2 kDa as compared to wild type. Dramatically reduced binding of CCL4; when associated with A-7; A-16; A-17. Similar molecular mass loss. Dramatically reduced binding of CCL4; when associated with A-7 only
	Mutagenesis	7	1	S → A: No change in glycosylation status and binds CCL4 as efficiently as wild type. Loss of molecular mass of about 2 kDa as compared to wild type. Dramatically reduced binding of CCL4; when associated with A-6; A-16; A-17. Similar molecular mass loss. Dramatically reduced binding of CCL4; when associated with A-6 only
	Mutagenesis	10	1	Y → F: No sulfation and greatly decreases binding of CCL4 and CCL5; when associated with F-3; F-14 and F-15. Small loss of sulfation; when associated with F-14 and F-15
	Mutagenesis	14	1	Y → D: No sulfation and greatly decreased binding CCL4 and CCL5; when associated with D-3; D-10 and D-14. No restoration of CCL4 binding; when associated with D-10 and D-15
	Mutagenesis	14	1	Y → F: No sulfation and greatly decreases binding of CCL4 and CCL5; when associated with F-3; F-10; and F-15. Small loss of sulfation; when associated with F-10 and F-15
	Mutagenesis	15	1	Y → D: No sulfation and greatly decreased binding CCL4 and CCL5; when associated with D-3; D-10 and D-14. Restored most CCL4 binding; when associated with D-3 and D-10
	Mutagenesis	15	1	Y → F: No sulfation and greatly decreases binding of CCL4 and CCL5; when associated with F-3; F-10 and F-14. Small loss of sulfation; when associated with F-10 and F-14
	Mutagenesis	16	1	T → A: Similar decrease in molecular mass when treated with O-glycosidase as for wild type; when associated with A-17
	Mutagenesis	17	1	S → A: Similar decrease in molecular mass when treated with O-glycosidase as for wild type; when associated with A-16
	Mutagenesis	321	1	C → A: Small reduction in palmitoylation. Cell surface expression reduced by 50%. Greatly reduced palmitoylation. Cell surface expression greatly reduced; when associated with A-323 or A-324. No palmitoylation. Cell surface expression greatly reduced. HIV entry reduced by 50%; when associated with A-323 and A-324
	Mutagenesis	323	1	C → A: Small reduction in palmitoylation. Cell surface expression reduced by 50%. Greatly reduced palmitoylation. Cell surface expression greatly reduced; when associated with A-321 or A-324. No palmitoylation. Cell surface expression greatly reduced. HIV entry reduced by 50%; when associated with A-321 and A-324
	Mutagenesis	324	1	C → A: Small reduction in palmitoylation. Cell surface expression reduced by 50%. Greatly reduced palmitoylation. Cell surface expression greatly reduced; when associated with A-321 or A-323. No palmitoylation. Cell surface expression greatly reduced. HIV entry reduced by 50%; when associated with A-321 and A-323
	Mutagenesis	336	1	S → A: APO-RANTES-stimulated phosphorylation reduced by 15%; APO-RANTES-stimulated phosphorylation reduced by 30-50%; when associated with A-337 or A-342 or A-349; APO-RANTES-stimulated phosphorylation reduced by 80%; when associated with A-337 and A-342 or A-349; No APO-RANTES-stimulated phosphorylation; when associated with A-337; A-342 and A349
	Mutagenesis	337	1	S → A: APO-RANTES-stimulated phosphorylation reduced by 18%; APO-RANTES-stimulated phosphorylation reduced by 30-50% on APO-RANTES stimulation; when associated with A-336 or A-342 or A-349; APO-RANTES-stimulated phosphorylation reduced by 80%; when associated with A-336 and A-342 or A-349; No APO-RANTES-stimulated phosphorylation; when associated with A-336; A-342 and A349
	Mutagenesis	342	1	S → A: APO-RANTES-stimulated phosphorylation reduced by 42%. Phosphorylation reduced by 50% on APO-RANTES stimulation; when associated with A-336 or A-337 or A-349; APO-RANTES-stimulated phosphorylation reduced by 80% when associated with A-336 and A-337 or A-349; No APO-RANTES-stimulated phosphorylation; when associated with A-336; A-337 and A349
	Mutagenesis	349	1	S → A: APO-RANTES-stimulated phosphorylation reduced by 43%; APO-RANTES-stimulated phosphorylation reduced by 30-50%; when associated with A-336 or A-337 or A-342; APO-RANTES-stimulated phosphorylation reduced by 80%; when associated with A-336 and A-337 or A-342; No APO-RANTES-stimulated phosphorylation stimulation; when associated with A-336; A-337 and A347
Secondary structure