STUB1 - STIP1 Homology And U-Box Containing Protein | Elisa - Clia - Antibody - Protein

Background

STUB1, also known as CHIP (C-terminus of Hsc70 Interacting Protein), is a crucial E3 ubiquitin ligase that plays a significant role in protein quality control by interacting with chaperones HSP70 and HSP90. This interaction facilitates the ubiquitination and subsequent proteasomal degradation of misfolded or damaged proteins. STUB1 was identified as a protein that not only assists in chaperone-mediated protein folding but also in the regulation of protein turnover, making it essential for maintaining cellular homeostasis. Dysregulation of STUB1 is linked to various pathological conditions, including neurodegenerative diseases, cancer, and cardiac disorders.

Protein Structure

STUB1 is composed of distinct domains that enable its function:

• TPR (Tetratricopeptide Repeat) Domain: Located at the N-terminus, this domain facilitates interaction with HSP70 and HSP90 chaperones.
• U-Box Domain: Located at the C-terminus, this domain has E3 ubiquitin ligase activity, essential for tagging substrate proteins with ubiquitin for proteasomal degradation.
• Coiled-Coil Domain: Provides structural stability and facilitates dimerization, which is necessary for its functional activity.

Classification and Subtypes

STUB1 belongs to the U-box family of E3 ubiquitin ligases, characterized by the presence of a U-box domain that confers ubiquitin ligase activity. There are no known subtypes of STUB1, but it is part of a larger network of proteins involved in protein quality control and ubiquitination.

Function and Biological Significance

STUB1 plays several key roles in cellular physiology:

• Protein Quality Control: By interacting with chaperones, STUB1 assists in the identification and ubiquitination of misfolded or damaged proteins, targeting them for degradation by the proteasome.
• Regulation of Chaperone Function: STUB1 modulates the activity of HSP70 and HSP90, influencing their ability to fold client proteins.
• Stress Response: Under stress conditions, STUB1 expression is upregulated to enhance the cell's capacity to manage misfolded proteins.
• Cell Signaling and Apoptosis: STUB1 regulates various signaling pathways by targeting specific signaling proteins for degradation, thus influencing cell growth, differentiation, and apoptosis.

Clinical Issues

Aberrations in STUB1 function are associated with multiple diseases:

• Neurodegenerative Diseases: Mutations or dysfunctions in STUB1 are linked to disorders such as Alzheimer's, Parkinson's, and spinocerebellar ataxias, where the accumulation of misfolded proteins is a common pathological feature.
• Cancer: STUB1 can act as a tumor suppressor by promoting the degradation of oncogenic proteins. Altered STUB1 expression or activity can contribute to tumorigenesis.
• Cardiac Disorders: STUB1 is involved in cardiac proteostasis, and its dysfunction can lead to cardiac hypertrophy and heart failure.
• Inflammatory Diseases: STUB1 influences immune responses and inflammation by regulating the turnover of signaling proteins involved in these processes.

Summary

STUB1 (CHIP) is a pivotal E3 ubiquitin ligase and co-chaperone protein essential for maintaining protein quality control within cells. Comprising TPR and U-box domains, STUB1 interacts with chaperones like HSP70 and HSP90 to identify and tag misfolded proteins for degradation. It plays a significant role in stress response, cell signaling, and apoptosis. Dysregulation of STUB1 is implicated in a variety of diseases, including neurodegenerative disorders, cancer, and cardiac diseases. Understanding the mechanisms of STUB1 function and regulation provides insights into potential therapeutic strategies for these conditions.