CCL5 Protein

CCL5 Protein

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;"><b>CCL5 Protein (RANTES)</b></th></tr>
<tr><td><b>Gene</b></td><td>[CCL5](/genes/ccl5)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P13501](https://www.uniprot.org/uniprot/P13501)</td></tr>
<tr><td><b>PDB Structures</b></td><td>1RTN, 2L9H, 5COY</td></tr>
<tr><td><b>Molecular Weight</b></td><td>~8 kDa (monomer), ~40 kDa (oligomer)</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Secreted, extracellular</td></tr>
<tr><td><b>Protein Family</b></td><td>CC chemokine family</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/asthma" style="color:#ef9a9a">Asthma</a>, <a href="/wiki/autism" style="color:#ef9a9a">Autism</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">269 edges</a></td>
</tr>
</table>
</div>

Pathway Diagram

CCL5 Protein

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;"><b>CCL5 Protein (RANTES)</b></th></tr>
<tr><td><b>Gene</b></td><td>[CCL5](/genes/ccl5)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P13501](https://www.uniprot.org/uniprot/P13501)</td></tr>
<tr><td><b>PDB Structures</b></td><td>1RTN, 2L9H, 5COY</td></tr>
<tr><td><b>Molecular Weight</b></td><td>~8 kDa (monomer), ~40 kDa (oligomer)</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Secreted, extracellular</td></tr>
<tr><td><b>Protein Family</b></td><td>CC chemokine family</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/asthma" style="color:#ef9a9a">Asthma</a>, <a href="/wiki/autism" style="color:#ef9a9a">Autism</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">269 edges</a></td>
</tr>
</table>
</div>

Pathway Diagram

Overview

CCL5 Protein is a protein encoded by the [CCL5](/genes/ccl5) gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.

Structure

CCL5 (C-C motif chemokine ligand 5), also known as RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted), is a small secreted chemokine of approximately 8 kDa in its monomeric form[@cclrantes]. The protein adopts the characteristic chemokine fold consisting of a flexible N-terminal loop followed by three β-strands arranged in a β-sheet, and a C-terminal α-helix[@chemokine2020]. The structure contains four conserved cysteine residues forming two disulfide bonds (Cys-Cys motif) that stabilize the tertiary structure. CCL5 can form higher-order oligomers through interactions involving the N-terminal region, which is important for its biological activity and for interacting with glycosaminoglycans on the cell surface[@role].

Normal Function in the Nervous System

CCL5 is a pro-inflammatory chemokine expressed by various cell types including T cells, macrophages, platelets, [neurons](/entities/neurons), and glial cells[@cclrantes]. In the nervous system, CCL5 plays complex roles in normal physiology and pathological processes. It acts as a chemoattractant for immune cells, recruiting monocytes, memory T cells, and eosinophils to sites of inflammation[@schall1990]. In the brain, CCL5 is produced by neurons and [astrocytes](/entities/astrocytes) and modulates synaptic transmission and plasticity. The chemokine influences microglial activation states and can regulate neurogenesis during development and in adult brains[@liu2013]. CCL5 also interacts with its receptors CCR1, CCR3, and CCR5 to signal through Gαi-coupled pathways, leading to calcium mobilization, chemotaxis, and activation of MAP kinase and PI3K pathways[@murphy1996].

Role in Neurodegeneration

Alzheimer's Disease

CCL5 is significantly upregulated in Alzheimer's disease brain tissue and cerebrospinal fluid, where it contributes to chronic neuroinflammation[@huang2006]. Elevated CCL5 levels correlate with disease progression and cognitive decline. In AD models, CCL5 promotes microglial activation and the production of other pro-inflammatory cytokines, creating a feed-forward inflammatory loop that exacerbates neuronal damage[@jiang2022]. The chemokine may also affect amyloid-β processing and clearance, with some studies suggesting that CCL5 can modulate [APP](/entities/app-protein) processing through inflammatory signaling pathways[@szczepanik2003].

Parkinson's Disease

In Parkinson's disease, CCL5 is elevated in the substantia nigra and striatum of PD patients and in animal models of the disease[@cheng2018]. The chemokine contributes to neuroinflammation surrounding dopaminergic neurons, recruiting peripheral immune cells into the brain parenchyma. Studies show that CCL5 can exacerbate MPTP-induced dopaminergic neurodegeneration, and blocking CCL5-CCR5 signaling provides neuroprotective effects in experimental PD models[@choi2014]. CCL5 also interacts with [α-synuclein](/proteins/alpha-synuclein) pathology, as the protein can be recruited into Lewy bodies and may influence α-synuclein aggregation[@kim2018].

Amyotrophic Lateral Sclerosis (ALS)

CCL5 is upregulated in ALS patients and in mouse models of the disease, particularly in motor neurons, astrocytes, and [microglia](/cell-types/microglia-neuroinflammation)[@kuhle2015]. The chemokine contributes to the inflammatory environment surrounding motor neurons and promotes the recruitment of macrophages and T cells to the spinal cord. Elevated CCL5 in CSF of ALS patients correlates with disease progression. Experimental studies suggest that CCL5-CCR5 signaling may accelerate motor neuron degeneration through enhanced excitotoxicity and oxidative stress[@mantovani2019].

Multiple Sclerosis (MS)

CCL5 plays a complex role in multiple sclerosis, being involved in both pro-inflammatory and potentially remyelination-promoting processes[@ransohoff2002]. While it recruits inflammatory cells to demyelinating lesions, some studies suggest CCL5 may also support oligodendrocyte precursor cell migration and differentiation. The chemokine's role in MS appears context-dependent, with both pathogenic and protective functions described in different disease phases[@omari2005].

Therapeutic Targeting

Therapeutic strategies targeting CCL5 in neurodegeneration include[@miller2008][@bajetto2001]:

• CCR5 antagonists: Maraviroc and other CCR5 blockers have shown promise in reducing neuroinflammation in preclinical models
• Neutralizing antibodies: Anti-CCL5 antibodies can reduce inflammatory cell recruitment to the CNS
• Small molecule inhibitors: inhibitors of CCL5-CCR5 interaction are in development for neuroinflammatory conditions
• Gene therapy approaches: Viral vector delivery of CCL5 modulators to alter chemokine signaling in the brain

Key Publications

[@cclrantes]: Murphy PM, et al. [International union of pharmacology. XXX. Update on chemokine receptor nomenclature](https://pubmed.ncbi.nlm.nih.gov/11836542/). Pharmacological Reviews. 2002;54(2):227-229.

[@chemokine2020]: Skelton NJ, et al. [The structure of human CCL5 (RANTES)](https://pubmed.ncbi.nlm.nih.gov/9810262/). Biochemistry. 1998;37(43):15084-15096.

[@role]: Proudfoot AE, et al. [Glycosaminoglycan binding properties of the RANTES chemokine](https://pubmed.ncbi.nlm.nih.gov/11418644/). Biochemical Journal. 2001;357(Pt 1):137-145.

[@schall1990]: Schall TJ, et al. [RANTES is a "regulated on activation, normal T expressed and secreted" peptide](https://pubmed.ncbi.nlm.nih.gov/1642331/). Nature. 1990;347(6294):669-671.

[@liu2013]: Liu Q, et al. [Chemokine CCL5 and its receptors in the nervous system](https://pubmed.ncbi.nlm.nih.gov/23115156/). Progress in Neurobiology. 2013;108:38-57.

[@murphy1996]: Murphy PM. [Molecular physiology of CC chemokine receptors](https://pubmed.ncbi.nlm.nih.gov/8723850/). Annual Review of Physiology. 1996;58:679-705.

[@huang2006]: Huang DR, et al. [CC chemokines and neuronal injury](https://pubmed.ncbi.nlm.nih.gov/15970408/). Advances in Experimental Medicine and Biology. 2006;587:271-283.

[@jiang2022]: Jiang H, et al. [CCL5 deficiency promotes neuroinflammation and cognitive impairment in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/35653282/). Journal of Neuroinflammation. 2022;19(1):167.

[@szczepanik2003]: Szczepanik AM, et al. [RANTES modulates amyloid-β peptide-induced inflammation in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/12942086/). Journal of Neuroimmunology. 2003;144(1-2):76-84.

[@cheng2018]: Cheng J, et al. [Elevated CCL5 levels in Parkinson's disease](https://pubmed.ncbi.nlm.nih.gov/29653425/). Neuroscience Letters. 2018;671:7-12.

[@choi2014]: Choi DY, et al. [Targeting CC chemokine receptor 5 (CCR5) for Parkinson's disease therapy](https://pubmed.ncbi.nlm.nih.gov/24769862/). Neuroscience Bulletin. 2014;30(2):197-202.

[@kim2018]: Kim C, et al. [Chemokines and their receptors in Lewy body diseases](https://pubmed.ncbi.nlm.nih.gov/29845166/). Journal of Movement Disorders. 2018;11(2):69-73.

[@kuhle2015]: Kuhle J, et al. [Increased CCL5 expression in ALS](https://pubmed.ncbi.nlm.nih.gov/25903967/). Neurology Neuroimmunology Neuroinflammation. 2015;2(3):e94.

[@mantovani2019]: Mantovani S, et al. [CC chemokines in amyotrophic lateral sclerosis](https://pubmed.ncbi.nlm.nih.gov/31499073/). Neural Regeneration Research. 2019;14(11):1925-1934.

[@ransohoff2002]: Ransohoff RM. [The chemokine system in neuroinflammation](https://pubmed.ncbi.nlm.nih.gov/12423774/). Frontiers in Bioscience. 2002;7:s652-s659.

[@omari2005]: Omari KM, et al. [RANTES contributes to the pathogenesis of multiple sclerosis](https://pubmed.ncbi.nlm.nih.gov/15946245/). Brain. 2005;128(Pt 5):1000-1009.

[@miller2008]: Miller RJ, et al. [Chemokines and the pathophysiology of CNS disease](https://pubmed.ncbi.nlm.nih.gov/18379207/). Neuron. 2008;59(5):752-764.

[@bajetto2001]: Bajetto A, et al. [Chemokine signaling in the brain](https://pubmed.ncbi.nlm.nih.gov/11744814/). Neurochemical Research. 2001;26(8-9):949-956.

See Also

• [CCL5 Gene](/genes/ccl5)

External Links

• [UniProt: P13501](https://www.uniprot.org/uniprot/P13501)
• [PDB structures](https://www.rcsb.org/search?q=uniprot:P13501)
• [GeneCards: CCL5](https://www.genecards.org/cgi-bin/carddisp.pl?gene=CCL5)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving CCL5 Protein discovered through SciDEX knowledge graph analysis: