KLK10

KEAP1

The Kelch-like ECH-associated protein 1 (KEAP1) is a crucial regulatory protein involved in the cellular response to oxidative stress. It functions primarily as a sensor for reactive oxygen species (ROS) and plays a significant role in the regulation of the Nrf2 (Nuclear factor erythroid 2-related factor 2) pathway, which is essential for maintaining cellular redox homeostasis.

Structure

KEAP1 is a cysteine-rich protein that contains several important domains:

• BTB Domain: The Broad-Complex, Tramtrack, and Bric-à-brac (BTB) domain is involved in dimerization and interaction with Cullin 3 (CUL3), a component of the E3 ubiquitin ligase complex.
• IVR Domain: The intervening region (IVR) contains several cysteine residues that are critical for sensing oxidative stress.
• Kelch Repeats: These are six Kelch motifs that form a β-propeller structure, which is responsible for binding to Nrf2.

Function

KEAP1 acts as a negative regulator of the Nrf2 pathway. Under normal conditions, KEAP1 binds to Nrf2 in the cytoplasm, promoting its ubiquitination and subsequent degradation by the proteasome. This process is mediated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex.

When cells are exposed to oxidative stress or electrophilic compounds, critical cysteine residues in KEAP1 are modified, leading to a conformational change that disrupts the KEAP1-Nrf2 interaction. As a result, Nrf2 is stabilized and translocates to the nucleus, where it activates the transcription of antioxidant response element (ARE)-driven genes. These genes encode for various cytoprotective proteins, including glutathione-S-transferases, NAD(P)H:quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1).

Clinical Significance

Mutations or alterations in KEAP1 can lead to dysregulation of the Nrf2 pathway, which has been implicated in several diseases:

• Cancer: Loss-of-function mutations in KEAP1 can result in constitutive activation of Nrf2, providing cancer cells with a survival advantage by enhancing their antioxidant capacity.
• Neurodegenerative Diseases: Impaired KEAP1 function can affect neuronal survival and has been linked to conditions such as Parkinson's disease and Alzheimer's disease.
• Chronic Obstructive Pulmonary Disease (COPD): Altered KEAP1-Nrf2 signaling is associated with the pathogenesis of COPD due to increased oxidative stress in lung tissues.

Research and Therapeutic Potential

Targeting the KEAP1-Nrf2 pathway is a promising therapeutic strategy for diseases characterized by oxidative stress. Small molecules that disrupt the KEAP1-Nrf2 interaction or modulate KEAP1 activity are being investigated for their potential to enhance cellular antioxidant defenses.

Also see

• Nrf2
• Oxidative stress
• Ubiquitin-proteasome system
• Antioxidant response element