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Scientists have uncovered how an important cellular enzyme is regulated, revealing new insights into the fundamental biological processes controlling gene expression and opening up potential avenues for future cancer drug development.
A team led by scientists at The Institute of Cancer Research, London, has revealed for the first time the structure and behaviour of the active form of an essential protein known as CDK11, which is known to be required for the growth of cancer cells. The researchers also identified a new mechanism that allows the enzyme to regulate its own activity.
The study, published in Nature Communications, was funded by The Institute of Cancer Research (ICR) – which is both a research institute and charity – with additional support provided through a Medical Research Council Career Development Award to senior author Dr Basil Greber.
Addressing a longstanding question
Cyclin-dependent kinases (CDKs) are a family of enzymes that regulate essential cellular processes and are vital for normal cell function. However, cancer cells can become reliant on them to grow and divide. While several CDKs have been extensively studied and successfully targeted with drugs, others, including CDK11, remain less well understood.
As CDK11 controls multiple key cellular pathways, it has vital roles in cell division, gene transcription, as well as RNA splicing – a process that allows cells to edit and refine genetic instructions before they are used to make proteins. These are essential steps for cellular function, yet disruptions to this editing process are becoming increasingly linked to cancer and other diseases.
Although researchers have long known that CDK11 is required to activate cellular mechanisms responsible for RNA splicing – which is done through spliceosomes – exactly how the active CDK11 complex is assembled and regulated has remained unclear.
To bridge this knowledge gap, the research team used cryo-electron microscopy (cryo-EM) – an advanced imaging technique capable of visualising biological molecules at near-atomic resolution. By applying cryo-EM to these relatively small protein complexes, the team was able to view and capture detailed snapshots of CDK11 in action.
The architecture of the active CDK11 complex
The researchers focused on a three-part protein complex made up of CDK11 and the regulatory proteins cyclin L and SAP30BP, forming the active unit driving spliceosome activation.
They found that SAP30BP plays a central part in stabilising the complex. Without it, cyclin L becomes unstable and is unable to fulfil its role in supporting CDK11 function. By wrapping around cyclin L, SAP30BP effectively holds the complex together and enables it to assemble correctly.
The study also revealed how these three components interact at a molecular level, providing a detailed map of the interactions allowing the complex to function. These new insights are helping to explain how CDK11 becomes activated and how it carries out its role in RNA splicing.
A unique mechanism of self-regulation
Enzymes like CDK11 usually work by binding to other target molecules, known as substrates. But in this study, the research team discovered that part of CDK11 acts like a decoy – mimicking a normal target and blocking the enzyme’s active site.
The identification of this pseudo-substrate is one of the study’s most significant findings. By occupying this active site, the pseudo-substrate prevents other molecules from accessing CDK11, acting as a built-in brake that allows the enzyme to regulate its own activity.
Importantly, this is the first time that a decoy mechanism has been identified in a cyclin-dependant kinase. While similar mechanisms are known in other enzyme families, its discovery in CDK11 represents a notable advance in understanding how these proteins are controlled.
The team also found evidence that chemical modifications to this pseudo-substrate may influence how strongly it blocks the enzyme, providing an additional layer of regulation.
Implications for drug development
Although the study focuses on fundamental biology, the findings have important long-term implications for cancer research. CDK11 activity is required for the growth of multiple cancer cell types, making it an emerging target for drug development.
First author Amy McGeoch, a PhD student in the Structural Biology of DNA Repair Complexes Group at the ICR, said: “We’re excited about how these new insights could help guide the design of more selective and effective drugs targeting CDK11, with the long-term goal of developing new cancer treatments. However, our work represents an early-stage step, focused on uncovering the basic mechanisms with further research required to translate our findings into clinical applications.”
Future steps
The team plans to continue investigating how CDK11 is regulated and how the newly identified pseudo-substrate influences its activity in different cellular contexts. Future research will include biochemical studies to further characterise this regulatory mechanism, as well as further structural studies of CDK11 within larger molecules assemblies involved in gene expression.
Senior author Dr Greber, Group Leader of the Structural Biology of DNA Repair Complexes Group, said: “While it’s too early to estimate the number of patients who might benefit from this research, the study provides an important foundation for future work aimed at targeting CDK11 in cancer.
“By revealing the detailed inner workings of this complex enzyme, our research contributes to a growing understanding of how gene expression is controlled – and how these processes might one day be manipulated for therapeutic benefit.”
Image credit: Pavlofox from Pixabay (modified)
