Nature Sub-Journal: Formyl Peptide Receptor Structure Brings New Opportunities for Alzheimer's Drug Development

Formyl peptide receptors (FPRs) belong to the superfamily of G protein-coupled receptors (GPCRs) that recognize danger signals from pathogens or damaged tissues in the early stages of an immune response ( Such as: formyl peptides released by bacteria or mitochondria, etc.
), causing neutrophils to migrate and infiltrate
.

The human body contains three FPRs (FPR1-3)
.

Among them, FPR1 and FPR2 are closely related to inflammation, multiple sclerosis and neurodegenerative diseases
.

One of the main pathological features of Alzheimer's disease (AD) is senile plaques (SP) located outside neurons in the cerebral cortex and hippocampus.
Senile plaques are mainly composed of beta amyloid-42 (Aβ42).
Previous studies have found that Aβ42 can mediate its cytotoxicity by binding to FPR2
.

In addition, FPR2 also acts as a receptor for the neuroprotective peptide humanin, which protects nerve cells from Aβ42 damage
.

These studies have shown that FPR2 plays an important role in the occurrence and development of AD, but the related molecular mechanism has not been clear
.

Recently, Wu Beili's research group and Zhao Qiang's research group of Shanghai Institute of Materia Medica, Chinese Academy of Sciences have made a breakthrough in the study of FPR structure.
The ligand binding mode and receptor function regulation mechanism were studied, and the molecular mechanism of FPR2-mediated Aβ42 nerve injury and humanin neuroprotection was elucidated for the first time at the atomic level
.

In addition, the research team also determined the electron microscope structures of the complexes of FPR1 and FPR2 bound to different formyl peptides, revealing the ligand-selective mechanism of these two FPRs
.

These studies provide an important basis for in-depth understanding of the important role of FPR in AD and other inflammatory diseases, which will help the drug development of related diseases
.

The research paper will be published in the internationally renowned academic journal Nature Communications on April 1, 2022, Beijing time under the title "Structural basis of FPR2 in recognition of Aβ42 and neuroprotection by humanin"
.

The complex structure of FPR2 and Aβ42 shows that the N-terminal region of Aβ42 plays a major role in binding to FPR2, and its head protrudes into the binding pocket of the FPR2 transmembrane domain to form a polar role with the transmembrane helix; the tail Binds to the extracellular region of the receptor through hydrophobic interactions
.

The C-terminus of Aβ42 assists its binding to receptors mainly by stabilizing the conformation of the N-terminal region
.

Further functional studies found that the ability of the receptor to be activated by Aβ42 was significantly reduced after key amino acid mutations at the interface between FPR2 and Aβ42, indicating that the correct recognition of FPR2 and Aβ42 is crucial for receptor function
.

Aβ42 exists in a variety of conformational states in the body.
The above findings indicate that only when Aβ42 has a specific conformation can FPR2 be activated, thereby triggering inflammatory responses and neurotoxicity.
Mechanisms provide the structural basis
.

The neuroprotective peptide humanin protects neural cells from Aβ42-induced neural apoptosis
.

This time, the researchers found that most of the binding sites of humanin and Aβ42 in FPR2 overlap, but humanin has a stronger interaction with the receptor, which enables it to effectively block Aβ42 and the receptor by occupying the binding site.
, thereby inhibiting the inflammatory response and fibrotic aggregation of intracellular Aβ42
.

This provides an important basis for explaining the molecular mechanism of humanin's neuroprotective effect
.

Schematic diagram of the structure of the formyl peptide receptor FPR2
.

FPR2 is closely related to inflammation, multiple sclerosis and neurodegenerative diseases
.

The gray ribbons below the figure show the complex structure of FPR2 and formylated humanin (left) and the complex structure of FPR2 and Aβ42 (right).
Aβ42 and humanin are represented by orange and green surface maps, respectively
.

(Photo provided by Beili Wu’s research group) FPR1 and FPR2 play important roles in host defense and inflammatory responses by binding to formyl peptides derived from bacteria or mitochondria, but these two FPRs are highly specific for the recognition of formyl peptides sex
.

FPR1 selectively recognizes short-chain formyl peptides with smaller molecular weights, whereas FPR2 tends to bind longer-chain formyl peptides with larger molecular weights
.

Comparing the complex structures of FPR1 and FPR2 with different formyl peptides, it was found that the difference in charge within the ligand-binding pockets of the two receptors and the openness of the extracellular regions of the receptors determine the ligand selectivity
.

Compared with FPR1, the opening of the extracellular region of FPR2 is larger, which provides sufficient space for binding peptides and protein ligands with larger molecular weight, making FPR2 the most diverse GPCR of ligands discovered so far
.

This study systematically revealed the specific recognition mechanism of formyl peptide receptors for many different types of ligands, elucidated the regulatory mechanism of FPR in inflammatory and neurodegenerative diseases, and will facilitate the development of novel disease treatment strategies
.
The first authors of this study include assistant researcher Zhu Ya, master student Zong Xin, associate researcher Han Shuo ,
and Ph.
D.
The research work has received financial support from the National Natural Science Foundation of China, the Ministry of Science and Technology, the Chinese Academy of Sciences, and the Shanghai Municipal Science and Technology Commission
.

Link to the full text https:// Contributing Department | Wu Beili Research Group