# C5AR1

## Overview
C5AR1 is the gene encoding the complement C5a receptor 1 (C5aR1), a Class A G protein-coupled receptor (GPCR) integral to the immune system's response to inflammation and infection. The C5aR1 protein is primarily involved in mediating the effects of the complement component C5a, a potent inflammatory peptide, by facilitating a cascade of immune responses. This receptor is characterized by its seven-transmembrane domain structure typical of GPCRs and is predominantly expressed on myeloid cells and various non-immune cells, underscoring its broad role in immune surveillance and response (Li2020Pharmacological). The interaction of C5a with C5aR1 not only triggers inflammatory signaling pathways but also plays a critical role in the pathogenesis of numerous inflammatory and autoimmune diseases, making it a significant target for therapeutic intervention (Pandey2020Emerging).

## Structure
C5AR1, or complement component 5a receptor 1, is a G protein-coupled receptor (GPCR) characterized by a seven-transmembrane (7TM) helix architecture, typical of the rhodopsin family of GPCRs (Pandey2020Emerging). The receptor features extracellular loops (ECLs) and intracellular loops (ICLs) that play crucial roles in ligand binding and receptor activation. Notably, the extracellular loop 2 (ECL2) adopts a β-hairpin secondary structure essential for the recognition of ligands such as C5a and synthetic peptide C5a pep (Feng2023Mechanism).

The molecular structure of C5aR1 has been elucidated through various high-resolution techniques, including cryo-electron microscopy (cryo-EM) and X-ray crystallography. These studies have revealed detailed interactions at the ligand-receptor interface, involving key residues within the transmembrane domains and extracellular loops that stabilize the ligand-receptor complex through hydrogen bonds and hydrophobic interactions (Pandey2020Emerging; Feng2023Mechanism).

In terms of quaternary structure, the receptor has been observed in both monomeric and dimeric states, although the physiological relevance of the dimeric arrangement seen in some crystal structures is still under investigation (Pandey2020Emerging). The interaction with G proteins is mediated through specific contacts involving the cytoplasmic ends of transmembrane segments and intracellular loops, which undergo significant conformational changes upon ligand binding to facilitate downstream signaling (Saha2023Structural). 

These structural insights are crucial for understanding the receptor's function in immune response and for the development of therapeutic agents targeting C5aR1.

## Function
The C5AR1 gene encodes the complement C5a receptor 1 (C5aR1), a Class A G protein-coupled receptor (GPCR) that plays a pivotal role in the immune system by mediating responses to the complement fragment C5a, a key effector of complement activation. Upon binding with its ligand, C5a, C5aR1 activates several downstream signaling pathways crucial for immune cell function. These include the inhibition of cAMP/protein kinase A signaling, activation of extracellular signal-regulated kinase 1/2 (ERK1/2), and recruitment of β-arrestins, which facilitate various cell-type-specific responses such as chemotaxis, phagocytosis, and cytokine release (Li2020Pharmacological).

C5aR1 is primarily expressed on myeloid cells, selected lymphocytes, and many non-immune cells, indicating its widespread importance in immune regulation and inflammation. The receptor's activation is predominantly coupled to the Gα i2 protein, and it plays a crucial role in inflammatory responses, making it a target for pharmacological intervention to manage inflammation associated with various inflammatory and neurodegenerative diseases (Li2020Pharmacological).

Moreover, C5aR1 undergoes phosphorylation in its carboxyl terminus upon agonist binding, which facilitates the recruitment of β arrestins. This recruitment is important for receptor internalization and signaling modulation, although the exact role of β arrestins in C5aR1 signaling is not fully established (Pandey2020Emerging). The receptor's ability to couple with Gαi and β arrestins, despite its unique structural features like the reverse orientation of Helix 8, highlights its robust functional versatility and its crucial role in controlling inflammation and immune response (Pandey2020Emerging).

## Clinical Significance
C5AR1, or complement C5a receptor 1, is implicated in various diseases and conditions due to mutations, alterations in expression, or disruptions in its normal interactions. In Alzheimer's disease (AD), the genetic deletion or pharmacological inhibition of C5AR1 has shown protective effects against cognitive decline and neuronal injury, suggesting its significant role in the disease's progression (Hernandez2017Prevention; Carvalho2022Modulation). Similarly, in renal ischemia/reperfusion injury, C5AR1 deficiency leads to reduced inflammation and fibrosis, indicating its involvement in renal pathologies (Peng2019The).

C5AR1 also plays a role in autoimmune diseases such as bullous pemphigoid, where it mediates inflammatory responses in skin lesions (Emtenani2022Differential). Furthermore, its expression is linked to various cancer types, affecting survival rates and responses to therapies. High expression levels of C5AR1 are associated with resistance to chemotherapy and worse outcomes in immune checkpoint blockade therapies, particularly in melanoma and bladder cancer (Lawal2021Pan-Cancer).

These findings underscore the clinical significance of C5AR1 in a range of inflammatory and immune-related conditions, highlighting its potential as a target for therapeutic interventions.

## Interactions
C5AR1, also known as complement C5a receptor 1, is a G protein-coupled receptor (GPCR) that interacts with the complement component C5a. This interaction is crucial for the receptor's function in immune responses, including inflammation and cell activation. The receptor engages with the Gαi subfamily of heterotrimeric G proteins upon C5a binding, leading to a cascade of intracellular signaling events such as the inhibition of cAMP levels and mobilization of intracellular calcium ions (Pandey2019Partial; Pandey2020Emerging). Additionally, C5aR1 undergoes phosphorylation, which facilitates the recruitment of β-arrestins. This recruitment is essential for receptor internalization and plays a role in modulating receptor signaling (Pandey2019Partial).

Structural studies have shown that C5aR1 interacts with C5a through a two-site binding model involving the N-terminus and possibly the second extracellular loop of the receptor (Siciliano1994Two-site). Furthermore, the receptor forms complexes with various ligands and proteins, as evidenced by cryo-electron microscopy studies, which reveal the interaction details and conformational changes upon ligand binding (Feng2023Mechanism).

These interactions not only trigger signaling pathways but also influence the receptor's structural configuration, affecting its binding affinity and signaling efficacy (Feng2023Mechanism).


## References


[1. (Peng2019The) Qi Peng, Weiju Wu, Kun-Yi Wu, Bo Cao, Cui Qiang, Ke Li, Steven H. Sacks, and Wuding Zhou. The c5a/c5ar1 axis promotes progression of renal tubulointerstitial fibrosis in a mouse model of renal ischemia/reperfusion injury. Kidney International, 96(1):117–128, July 2019. URL: http://dx.doi.org/10.1016/j.kint.2019.01.039, doi:10.1016/j.kint.2019.01.039. (49 citations) 10.1016/j.kint.2019.01.039](https://doi.org/10.1016/j.kint.2019.01.039)

[2. (Pandey2019Partial) Partial ligand-receptor engagement yields functional bias at the human complement receptor, C5aR1 (35 citations) 10.1101/515700](https://doi.org/10.1101/515700)

[3. (Saha2023Structural) Structural insights into ligand-recognition, activation, and signaling-bias at the complement C5a receptor, C5aR1 (2 citations) 10.1101/2023.01.14.524051](https://doi.org/10.1101/2023.01.14.524051)

[4. (Hernandez2017Prevention) Michael X. Hernandez, Shan Jiang, Tracy A. Cole, Shu-Hui Chu, Maria I. Fonseca, Melody J. Fang, Lindsay A. Hohsfield, Maria D. Torres, Kim N. Green, Rick A. Wetsel, Ali Mortazavi, and Andrea J. Tenner. Prevention of c5ar1 signaling delays microglial inflammatory polarization, favors clearance pathways and suppresses cognitive loss. Molecular Neurodegeneration, September 2017. URL: http://dx.doi.org/10.1186/s13024-017-0210-z, doi:10.1186/s13024-017-0210-z. (73 citations) 10.1186/s13024-017-0210-z](https://doi.org/10.1186/s13024-017-0210-z)

[5. (Emtenani2022Differential) Shirin Emtenani, Maike M. Holtsche, Richard Stahlkopf, Daniel L. Seiler, Timothy Burn, Huiqing Liu, Melissa Parker, Kaan Yilmaz, Hasan O. Dikmen, Markus Huber Lang, Christian D. Sadik, Christian M. Karsten, Nina van Beek, Ralf J. Ludwig, Jörg Köhl, and Enno Schmidt. Differential expression of c5ar1 and c5ar2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients. Frontiers in Immunology, November 2022. URL: http://dx.doi.org/10.3389/fimmu.2022.942493, doi:10.3389/fimmu.2022.942493. (4 citations) 10.3389/fimmu.2022.942493](https://doi.org/10.3389/fimmu.2022.942493)

[6. (Li2020Pharmacological) Xaria X. Li, John D. Lee, Nicholas L. Massey, Carolyn Guan, Avril A.B. Robertson, Richard J. Clark, and Trent M. Woodruff. Pharmacological characterisation of small molecule c5ar1 inhibitors in human cells reveals biased activities for signalling and function. Biochemical Pharmacology, 180:114156, October 2020. URL: http://dx.doi.org/10.1016/j.bcp.2020.114156, doi:10.1016/j.bcp.2020.114156. (51 citations) 10.1016/j.bcp.2020.114156](https://doi.org/10.1016/j.bcp.2020.114156)

[7. (Lawal2021Pan-Cancer) Bashir Lawal, Sung-Hui Tseng, Janet Olugbodi, Sitthichai Iamsaard, Omotayo Ilesanmi, Mohamed Mahmoud, Sahar Ahmed, Gaber Batiha, and Alexander Wu. Pan-cancer analysis of immune complement signature c3/c5/c3ar1/c5ar1 in association with tumor immune evasion and therapy resistance. Cancers, 13(16):4124, August 2021. URL: http://dx.doi.org/10.3390/cancers13164124, doi:10.3390/cancers13164124. (26 citations) 10.3390/cancers13164124](https://doi.org/10.3390/cancers13164124)

[8. (Pandey2020Emerging) Shubhi Pandey, Jagannath Maharana, Xaria X. Li, Trent M. Woodruff, and Arun K. Shukla. Emerging insights into the structure and function of complement c5a receptors. Trends in Biochemical Sciences, 45(8):693–705, August 2020. URL: http://dx.doi.org/10.1016/j.tibs.2020.04.004, doi:10.1016/j.tibs.2020.04.004. (66 citations) 10.1016/j.tibs.2020.04.004](https://doi.org/10.1016/j.tibs.2020.04.004)

[9. (Siciliano1994Two-site) S J Siciliano, T E Rollins, J DeMartino, Z Konteatis, L Malkowitz, G Van Riper, S Bondy, H Rosen, and M S Springer. Two-site binding of c5a by its receptor: analternative binding paradigm for g protein-coupled receptors. Proceedings of the National Academy of Sciences, 91(4):1214–1218, February 1994. URL: http://dx.doi.org/10.1073/pnas.91.4.1214, doi:10.1073/pnas.91.4.1214. (192 citations) 10.1073/pnas.91.4.1214](https://doi.org/10.1073/pnas.91.4.1214)

[10. (Carvalho2022Modulation) Klebea Carvalho, Nicole D. Schartz, Gabriela Balderrama-Gutierrez, Heidi Y. Liang, Shu-Hui Chu, Purnika Selvan, Angela Gomez-Arboledas, Tiffany J. Petrisko, Maria I. Fonseca, Ali Mortazavi, and Andrea J. Tenner. Modulation of c5a–c5ar1 signaling alters the dynamics of ad progression. Journal of Neuroinflammation, July 2022. URL: http://dx.doi.org/10.1186/s12974-022-02539-2, doi:10.1186/s12974-022-02539-2. (19 citations) 10.1186/s12974-022-02539-2](https://doi.org/10.1186/s12974-022-02539-2)

[11. (Feng2023Mechanism) Yuying Feng, Chang Zhao, Yue Deng, Heli Wang, Liang Ma, Sicen Liu, Xiaowen Tian, Bo Wang, Yan Bin, Peipei Chen, Wei Yan, Ping Fu, and Zhenhua Shao. Mechanism of activation and biased signaling in complement receptor c5ar1. Cell Research, 33(4):312–324, February 2023. URL: http://dx.doi.org/10.1038/s41422-023-00779-2, doi:10.1038/s41422-023-00779-2. (19 citations) 10.1038/s41422-023-00779-2](https://doi.org/10.1038/s41422-023-00779-2)