pH-Dependent recognition of apoptotic and necrotic cells by the human dendritic cell receptor DEC205
Longxing Cao1, Xiangyi Shi1, Haishuang Chang1
1National Center for Protein Science, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201210, China;
Abstract:
Dendritic cells play important roles in regulating innate and adaptive immune responses. DEC205 (CD205) is one of the major endocytotic receptors on dendritic cells and has been widely used for vaccine generation against viruses and tumors. However, little is known about its structure and functional mechanism. Here we determine the structure of the human DEC205 ectodomain by cryoelectron microscopy. The structure shows that the 12 extracellular domains form a compact double ring-shaped conformation at acidic pH and become extended at basic pH. Biochemical data indicate that the pH-dependent conformational change of DEC205 is correlated with ligand binding and release. DEC205 only binds to apoptotic and necrotic cells at acidic pH, whereas live cells cannot be recognized by DEC205 at either acidic or basic conditions. These results suggest that DEC205 is an immune receptor that recognizes apoptotic and necrotic cells specifically through a pH-dependent mechanism.
Insights
The DEC205 receptor on dendritic cells changes shape with pH, enabling it to bind apoptotic cells. This pH-dependent mechanism is crucial for immune responses against damaged cells.
Area of Science:
- Immunology
- Structural Biology
- Cell Biology
Background:
- Dendritic cells are key regulators of immune responses.
- DEC205 (CD205) is a major endocytotic receptor on dendritic cells, utilized in vaccine development.
- The structural and functional mechanisms of DEC205 remain largely uncharacterized.
Purpose of the Study:
- To determine the structure of the human DEC205 ectodomain.
- To elucidate the functional mechanism of DEC205, particularly its pH-dependent properties.
- To understand how DEC205 interacts with different cell types.
Main Methods:
- Cryoelectron microscopy was used to determine the 3D structure of the human DEC205 ectodomain.
- Biochemical assays were employed to investigate ligand binding and conformational changes.
- pH-dependent binding studies were conducted using various cell types (apoptotic, necrotic, live).
Main Results:
- The structure revealed a compact double ring conformation at acidic pH and an extended conformation at basic pH.
- DEC205 exhibits pH-dependent ligand binding and release.
- DEC205 specifically binds to apoptotic and necrotic cells at acidic pH, but not to live cells under any tested pH conditions.
Conclusions:
- DEC205 undergoes significant pH-dependent conformational changes.
- These conformational changes are directly linked to its ability to bind to apoptotic and necrotic cells.
- DEC205 functions as a specialized immune receptor, recognizing cellular debris through a pH-sensitive mechanism.
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