F-box protein

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PDB 1fs2 EBI

F-box protein refers to a family of proteins that play critical roles in cellular processes such as the cell cycle, signal transduction, and protein degradation. The name "F-box" is derived from the cyclin F protein, where the F-box motif was first identified. This motif is necessary for protein-protein interactions and is a component of the SCF complex (SKP1-CUL1-F-box protein), which functions in proteasome-mediated protein degradation.

Structure

The defining feature of F-box proteins is the F-box motif, a sequence of about 40-50 amino acids that facilitates binding with the protein SKP1. Beyond the F-box motif, these proteins can contain various other domains that determine the specificity of substrate recognition. These domains include the leucine-rich repeats (LRR), WD repeats, and the F-box associated domain (FBA). The diversity in these domains allows F-box proteins to target a wide range of substrates for ubiquitination and subsequent degradation.

Function

F-box proteins are best known for their role in the ubiquitin-proteasome system. They act as substrate recognition components of the SCF ubiquitin ligase complex, targeting proteins for ubiquitination and degradation. This process is crucial for regulating protein levels within the cell, affecting various cellular processes such as cell cycle progression, signal transduction, and gene expression.

In addition to their role in protein degradation, F-box proteins are involved in other cellular functions. For example, they participate in the regulation of apoptosis, DNA repair, and autophagy, highlighting their importance in maintaining cellular homeostasis and responding to stress.

Types of F-box proteins

F-box proteins can be classified based on the presence of specific domains besides the F-box motif. The main types include:

• FBXL proteins, which contain leucine-rich repeats (LRRs) and are involved in processes such as cell cycle control and signal transduction.
• FBXW proteins, which contain WD repeats and are implicated in various cellular functions, including histone methylation and circadian rhythm regulation.
• FBXO proteins, which contain other domains or no recognizable domains outside the F-box motif, and have diverse functions ranging from immune response regulation to developmental processes.

Clinical Significance

Mutations and dysregulation of F-box proteins have been linked to various diseases, including cancer, neurodegenerative diseases, and cardiovascular diseases. For instance, the overexpression of certain F-box proteins can lead to the degradation of tumor suppressor proteins, contributing to cancer progression. Conversely, the loss of function in F-box proteins involved in DNA repair can lead to genomic instability and tumorigenesis.

Research Directions

Research on F-box proteins continues to uncover their roles in cellular processes and their potential as therapeutic targets. Inhibitors of specific F-box proteins are being explored for the treatment of diseases such as cancer, where targeting the degradation pathway of oncogenic proteins may offer a therapeutic advantage.

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