EDEM1

EDEM1

Crystal structure of EDEM1 protein.

EDEM1 (ER degradation-enhancing alpha-mannosidase-like protein 1) is a protein involved in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. It plays a crucial role in the quality control of newly synthesized glycoproteins in the ER.

Structure

EDEM1 is a type II transmembrane protein, meaning it spans the ER membrane with its N-terminus in the ER lumen and its C-terminus in the cytoplasm. It consists of several functional domains, including a cytoplasmic domain, a transmembrane domain, and a luminal domain. The luminal domain contains a catalytic site responsible for the recognition and processing of misfolded glycoproteins.

Function

EDEM1 acts as an ERAD factor, facilitating the recognition and retrotranslocation of misfolded glycoproteins from the ER to the cytosol for degradation by the proteasome. It specifically recognizes and binds to glycoproteins with high-mannose oligosaccharides, which are indicative of misfolding. EDEM1 then recruits other ERAD components to form a complex that extracts the misfolded proteins from the ER membrane and delivers them to the proteasome for degradation.

Role in Protein Quality Control

The ER is responsible for folding and modifying newly synthesized proteins. However, due to various factors such as mutations, environmental stress, or errors in protein synthesis, misfolded proteins can accumulate in the ER. These misfolded proteins can be toxic to the cell and need to be eliminated to maintain cellular homeostasis. EDEM1 plays a crucial role in this process by identifying and targeting misfolded glycoproteins for degradation, preventing their accumulation and potential harm to the cell.

Clinical Implications

Mutations or dysregulation of EDEM1 have been associated with various diseases, including neurodegenerative disorders and cancer. In neurodegenerative diseases such as Alzheimer's and Parkinson's, impaired ERAD function can lead to the accumulation of misfolded proteins, contributing to disease progression. In cancer, EDEM1 dysregulation has been linked to altered protein quality control mechanisms, leading to increased cell survival and resistance to therapy.

References

1. C. Olivari, M. Molinari, "Glycoprotein folding and the role of EDEM1, EDEM2 and EDEM3 in degradation of folding-defective glycoproteins", FEBS Letters, vol. 581, no. 19, pp. 3658-3664, 2007. 2. S. Bernasconi, M. Molinari, "ERAD and ERAD tuning: disposal of cargo and of ERAD regulators from the mammalian ER", Current Opinion in Cell Biology, vol. 23, no. 2, pp. 176-183, 2011.

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