Ssutton: PTL Logic

Introduction

I am working to develop a new type of logic, called Post-Translational Logic, or PTL. PTL devices regulate the post-translational modifications of proteins to define system state and control cell function.

Current synthetic biological circuits make use of protein-DNA and RNA-RNA interactions to control gene expression in bacteria-- such circuits are examples of Transcrition-based Logic. A brief comparison of the two types of logic is as follows:

Transcription-based Logic

• Engineered around gene expression
• Typical parts: transcriptional regulators, translational regulators
• Typical signal: PoPS, resulting in desired cellular concentrations of proteins.
• Easier to engineer than PTL
• Slow response time (hours)
• Uses one subset of cellular functions

PTL

• Engineered around protein modifications
• Typical parts: kinases, phosphorylation sites, docking sites
• Typical signa: rate of modification, resulting in desired state of proteins.
• More difficult to engineer than Transcription-based logic.
• Fast response time (seconds)
• Explores a new set of applications

In designing PTL logic, I am working to answer the following questions:

• What is a PTL part?
• What is a PTL device?
• What signals are passed between devices?
• What are device performance specifications?

Below I will describe some of my ideas.

A Basic PTL System: Kinase-Kinase circuit

The most intuitive definition of a PTL device is illustrated as follows.

The problem with the above system is that the output of one device can only be received by a device that contains compatible Docking and PO4 parts. The figure below illustrates points of part-part interactions, with red line connecting parts that must be compatibile.

This trans-part compatibility defeats the purpose of a universal signal carrier, and limits the utility and versatility of PTL devices. Note that we encountered the same problem when defining PDL devices and signals.

A solution is to re-draw the device boundaries such that all corresponding parts are within the same devices:

Device 1 could be added upstream of any other device, and device part would be phosphorylated with maximal rate Vmax1.

Other types of devices: Localization

Phosphorylation controls many intracellular behaviors, including:

• allosteric activation (described by the MAP Kinases above) or inhibition
• translocation
• degradation
• protein complex formation
• other binding events

One of the largest challenges facing PTL is finding a signal carrier that can descrbie all of the above functions.

As an example, let's examine nuclear localization:

Thus far, I have shown two useful signal carriers: Vmax and Vnuc. Let's examine how the two signal carriers could be integrated into one circuit.

Combining Vmax and Vnuc into one circuit

Here is an example of a kinase that modulates the rate of transport of a Protein into the nucleus:

We could imagine a circuit in which an input device phosphorylates a downstream device on two Phosphorylation sites, thus resulting in two distinctive output signals:

Other types signals we might want to define and measure