Ubiquitinating a phosphorylated Cdk inhibitor on the blades of the Cdc4 beta-propeller
1Programs in Chemical Biology and Cancer Biology and Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
Cell
|January 30, 2003
Abstract:
Substrate binding by the SCFCdc4 ubiquitin ligase is regulated by phosphorylation. In this issue of Cell, Orlicky et al. describe the crystal structure of the Cdc4 subunit bound to a high-affinity substrate phosphopeptide. This structure provides insights into the binding interaction and how a precise mechanism involving multiple regulatory phosphorylations may be mediated by a single binding site.
Insights
Phosphorylation regulates substrate binding for the SCF-Cdc4 ubiquitin ligase. A new crystal structure reveals how Cdc4 binds a phosphorylated substrate, explaining regulatory mechanisms at a single site.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- The SCF-Cdc4 ubiquitin ligase complex plays a critical role in cell cycle regulation and protein degradation.
- Phosphorylation events are known to modulate the activity and substrate specificity of SCF-Cdc4.
- Understanding the precise molecular mechanisms of substrate recognition is crucial for deciphering cellular signaling pathways.
Purpose of the Study:
- To elucidate the structural basis of substrate binding by the Cdc4 subunit of the SCF-Cdc4 ubiquitin ligase.
- To investigate how phosphorylation regulates the interaction between Cdc4 and its high-affinity substrates.
- To provide insights into the mechanism by which multiple regulatory phosphorylations are coordinated at a single binding site.
Main Methods:
- X-ray crystallography was employed to determine the structure of the Cdc4 subunit.
- Cdc4 was crystallized in complex with a high-affinity substrate phosphopeptide.
- Structural analysis was performed to characterize the binding interface and interactions.
Main Results:
- The crystal structure of Cdc4 bound to a high-affinity phosphopeptide substrate was determined.
- Detailed insights into the specific binding interactions between Cdc4 and the phosphorylated substrate were obtained.
- The findings suggest a mechanism for how a single binding site can accommodate and be regulated by multiple phosphorylation events.
Conclusions:
- The determined structure provides a molecular understanding of how SCF-Cdc4 recognizes phosphorylated substrates.
- This work illuminates a precise mechanism for the regulation of ubiquitin ligase activity through phosphorylation.
- The findings have implications for understanding cell cycle control and protein turnover pathways.
Related Concept Videos
01:45Positive Regulator Molecules
To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.
02:39Positive Regulator Molecules
Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
02:34Inhibition of Cdk Activity
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
02:15M-Cdk Drives Transition Into Mitosis
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
00:50Anaphase Promoting Complex
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
02:34Inhibition of CDK Activity
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...