Furin: A Critical Cellular Protease in Health and Disease

Introduction

Furin, encoded by the FUR gene (also known as PCSK3), was the first discovered member of the proprotein convertase subtilisin/kexin (PCSK) family. Originally identified in 1990, furin has emerged as a central player in the proteolytic processing of numerous cellular proteins, including growth factors, hormones, and cell surface receptors. Its ubiquitous expression and diverse substrate specificity underscore its fundamental importance in cellular homeostasis.

Structure and Activation

Protein Structure

Furin is synthesized as a 794-amino acid zymogen that undergoes multiple processing steps for activation. The protein contains several distinct domains:

• An N-terminal signal peptide
• A prodomain (regulatory region)
• A catalytic domain containing the active site triad (Asp153, His194, and Ser368)
• A P domain essential for enzyme stability
• A cysteine-rich region
• A transmembrane domain
• A cytoplasmic tail

Activation Mechanism

The activation of furin involves a complex autocatalytic process occurring in multiple cellular compartments. Initially, the prodomain acts as an intramolecular chaperone, facilitating proper protein folding. Subsequently, a two-step autoproteolytic cleavage removes the prodomain, resulting in the mature, active enzyme.

Cellular Localization and Trafficking

Furin primarily localizes to the trans-Golgi network (TGN) but can cycle between multiple cellular compartments, including:

• The cell surface
• Endosomal compartments
• The TGN This trafficking is regulated by specific sorting signals in furin’s cytoplasmic domain and involves interactions with various adaptor proteins

Physiological Functions

Substrate Recognition

Furin recognizes and cleaves proteins at specific consensus sequences, typically R-X-K/R-R↓, where R represents arginine, K represents lysine, X represents any amino acid, and ↓ indicates the cleavage site. This sequence specificity ensures precise processing of target proteins.

Key Substrates and Processes

Furin processes numerous physiologically important substrates:

• Growth factors and hormones: Pro-β-NGF, Pro-BDNF, Pro-insulin
• Cell surface receptors: Insulin receptor, Notch receptors
• Matrix metalloproteinases
• Cell adhesion molecules
• Viral envelope proteins

Role in Disease

Cancer

Furin’s involvement in cancer progression is well-documented:

1. Activation of matrix metalloproteinases promoting metastasis
2. Processing of growth factors supporting tumor growth
3. Enhanced cell invasion and migration
4. Increased angiogenesis through VEGF processing

Infectious Diseases

Furin plays a crucial role in processing viral and bacterial proteins:

1. Viral glycoproteins required for infectivity
2. Bacterial toxins activation
3. Processing of viral envelope proteins, including those of influenza, HIV, and coronaviruses

Therapeutic Applications

Inhibitor Development

Recent efforts have focused on developing furin inhibitors as therapeutic agents:

1. Small molecule inhibitors
2. Peptide-based inhibitors
3. Protein-based inhibitors
4. Antibody-based approaches

Clinical Potential

Therapeutic targeting of furin shows promise in treating:

1. Various cancers
2. Viral infections
3. Bacterial infections
4. Metabolic disorders

Suitable ELISA Kits

• Furin ELISA Kit
• FUR ELISA Kit