Imagine you are a soldier on a very dangerous patrol in Afghanistan. While your conscious brain attends to the environment, looking for suspicious activity, the unconscious part of your brain is busy altering your body’s physiology in anticipation of an impending threat. Your heart will start to beat faster and much of your blood that would otherwise be traveling to your kidneys and digestive organs is rerouted to your muscles and nervous system. The liver dumps extra sugar into your blood and the airways in your lungs open wider, allowing them to deliver more oxygen to the blood that pulses more quickly. Your sweat glands are more active and the pupils of your eyes dilate. This is what is called the “fight or flight” response, made possible by the hormone epinephrine, better known as adrenalin. The net result of this response is that your muscles are stronger and faster and your brain is more alert. In other words, your body is optimized to fight the enemy, or if need be, to flee.
To get from the state of fear to a body that is better able to respond to fear, many signal “transitions” are involved. The awareness of a threat is “translated” into an electric current that travels along a distinct network of nerves known as the sympathetic nervous system. The electric current is then “translated” into a release of the hormone epinephrine. This hormone will then bind receptors on heart muscle cells, blood vessels cells, liver cells, etc. Thus cells will then “translate” the message of “epinephrine” into rising levels of cyclic AMP (cAMP) inside the cell. In other words, “fear” becomes high cellular concentrations of cAMP, which in turn activate a circuit of proteins to bring about altered cellular activity, which then results in the effects cited above.
The switch between a normal, unstressed physiological state and the stressed “fight-or-flight” state is thus the result of a series of molecular toggle switches being flipped in series. But perhaps the most important switch of them all is found within a class of proteins known as G-proteins. Why single out the G-proteins? Because they are the mediators between the environment outside the cell and the environment inside the cell. They convert the extracellular signal EPINEPHRINE into altered cell states.
G-proteins get their name from the fact that they both bind the substrate GTP and breakdown GTP into GDP and Pi. In fact, it is this activity that allows them to serve as molecular switches. How so? G-proteins can intrinsically cycle between active and inactive states in relationship to their substrate partner. When a G-protein binds GTP, it undergoes a conformational change and adopts an ACTIVE state. At this point, the GTP is ultimately hydrolyzed to GDP and Pi, resumes its original conformation, and becomes INACTIVE. While the cycle is intrinsic to G-proteins, it is usually the case that other proteins will interact with the G-proteins, either affecting the rate of hydrolysis or the rate of GDP release. Thus, these other proteins can modulate the switch between the two G-protein conformations. Put simply, they control the timing of the switch.
Let’s consider how the molecular switch works during the fight-or-flight response. Consider Figure 1.
Figure 1. G-proteins mediate generation of cAMP: a. G-protein bound to GDP binds to activated epinephrine receptor; b. G-protein bound to GTP interacts with adenylate cyclase and activates it.
Imagine this is the membrane of a liver cell. The hormone epinephrine (yellow) binds to the epinephrine receptor (blue). This binding induces a conformational change in the cytoplasmic part of the receptor, allowing it to bind to a G-protein (green)that is INACTIVE (bound to GDP). As a consequence of this interaction, the G-protein’s shape is altered, allowing it to release GDP. It then binds a fresh GTP and adopts the ACTIVE conformation, so that it can now diffuse laterally along the membrane and activate the enzyme, adenylate cyclase (dark orange). The adenylate cyclase can now begin to convert ATP molecules into cAMP, where the rising levels of cAMP are interpreted as signals to activate other enzymes. As for the activated G-protein? Within seconds, it breaksdown the GTP and becomes inactive, meaning that the adenylate cyclase is only activated for a brief moment.
While the explanation above is quite simplified, I hope it helps to convey the manner in which shape changes in concert with substrate binding can be coordinated to carry out a communication function. Remember, the outside signal EPINEPHRINE is converted into a signal that can be read and understood inside the cell – cAMP. And it’s the G-protein that acts as the switch between the two signals.
Another way to appreciate the essence of the G-protein is to strip it away from any particular biological context as seen in Figure 2.
Figure 2. The Stripped-Down G-protein Switch.
The G-protein exists in the “OFF” state (red) when it is bound to GDP. When it exchanges GDP for GTP, it is turned “ON” (green). When it hydrolyzes GTP to GDP and Pi, it turns OFF. We can thus think of it as a traffic light with its own intrinsic rate of switching. But what makes the G-protein such an immensely useful device is its vulnerability to modulation. GEFs (guanine nucleotide exchange factors) can facilitate the switch from OFF to ON. GAPs (GTPase activating proteins) can facilitate the switch from ON to OFF.
A couple of design-related points emerge from our brief consideration of the G proteins. The first is simple – an understanding of how G proteins work faintly echoes design. Here is yet another aspect of cell biology that easily converges with our thinking about technology, where a “switch” is used as part of a flow of information connecting the cytoplasm to the outside world in a meaningful way.
The second insight goes a little further. When you understand the potential utility of something like the G protein, you would have to ask why any designer would use it in only one situation? Clearly, such switches could be useful in a variety of situations and a variety of contexts, controlling the maze of complex interactions that exists within a cell. In other words, an understanding of the G protein’s role inside the cell leads us to predict common design from a teleological perspective. If the cell was designed, it would make no sense to design a completely novel switch every single time a switch is used. Instead, you would seek to use the same basic switch wherever it would function well. And this is exactly what we see in the cell, where G proteins are extensively used to control such things as protein synthesis, signal transduction, vesicle trafficking, cell division, and the reorganization of the cytoskeleton (many of these processes not only use switches, but also bolts). A variety of different types of G proteins, along with different GEFs and GAPs, are plugged into a variety of circuits.
Unfortunately, the concept of common design has a long history of post hoc use by antievolutionists. Nevertheless, the G proteins help us understand that common design is a reasonable expectation from any hypothesis that proposes life’s design. The problem is that it adds a lot of ambiguity to the picture. For example, a designer might be expected to select something like the G protein not only because it could be plugged into many contexts, but because it contained a certain level of evolvability, where it was well-suited to co-evolve with the developing circuit. So how do we distinguish the examples of derived G protein function from those that were originally designed?
One thing that is needed is a more objective approach to Common Design (CD). Instead of raising CD in an ad hoc fashion, we need some form of criteria that would be used to tentatively score something as ‘common design.’ For example, I can think of at least two criteria: 1) CD must exist in an overall design that is modular, such the common design can be viewed as the ‘same solution’ that is plugged into a ‘different context’ and 2) The “solution” should be seen in many different contexts. For example, if the putative CD is seen in only two situations, then the objection about designing different solutions carries more weight.
One final note. CDs could very well exist embedded within larger CDs. For example, the G proteins can be considered to fall under a larger umbrella of common design exhibited in what are known as the P-loop NTPases. Up to 18% of an organism’s genome may code for such NTPases. These proteins function to bind something like ATP or GTP and couple the breakdown of such molecules to the induction of conformational change in another partner. In other words, the P-loop NTPases play pivotal roles in many molecular machines – a common design.