How Period and Timeless Interact in Fruitflies
A brand new paper is making a splash in the field these days - so much that you can find the press release in three places: here, here and here, this last one being the coolest as it contains a movie and three podcasts!
One of the biggest problems in circadian biology is to account for such a long time - 24 hours - it takes for the whole transcription-translation feedback loop to run its course through a single cycle. Biochemical reactions tend to happen at much shorter time scales. Some mathematical models tried to invent possible mechanisms (with no basis in experimental findings), while molecular biologists, in general, tended to ignore the problem altogether.
Still, I have seen in a few talks over the years some evidence that some circadian clock gene mutations affect only a portion of the cycle. In other words, if a mutation makes the endogenous period in a mutant shorter than that in a wild type, it is not because the whole cycle runs faster, but because one phase of the cycle runs faster. If I remember correctly from various talks, it was almost always the late-afternoon/early-evening phase that got affected.
Now, Young, Saez and Meyer published a paper in Science that sheds some light on the problem. In the process, they also significantly alter the model of the Drosophila circadian clock. You can see the old model in a movie here (see if you can play the movie directly by clicking on this), actually a series of movies produced a couple of years ago. You can see the new model here:
The big difference (let's completely ignore a dozen other molecular players for now) is in the behavior of two core clock proteins: PERIOD and TIMELESS. It was believed, until now, that it takes about six hours for the two proteins to find each other in the cytoplasm and that once they do, they bind to each other (heterodimerize), which is neccessary for their entry into the nucleus where they act to activate expression of some genes and supress expression of some other genes. No need for complicated details now.
However, some very recent studies indicate that the two proteins break off from each other immediatelly before re-entering the nucleus, and they enter the nucleus alone, not as parts of a dimer.
What this new study does is demonstrate that the two proteins, as soon as they are formed, easily find each other and bind to each other, then sit idly in the cell for six hours before breaking off from each other and entering the nucleus. Also, mutations of Tim have no effect, while mutations of Per alter the duration the two proteins sit together as a dimer.
From the press release:
One caveat though. The ability of the dimer to stay together for six hours, and the ability of the Per mutations to alter this timing, are not neccessarily the inherent property of the dimer. In other words, it may not have anything to do with resembling properties of a crystal.
They may just as well be the result of interactions between the dimer and other proteins in the cell, some of which may be influenced by the signalling coming from other cells (e.g., from neighboring pacemaker neurons).
In other words, the ability of the dimer to stay put for six hours may be a property of the dimer, or it may be a property of the multicellular system as whole.
One of the biggest problems in circadian biology is to account for such a long time - 24 hours - it takes for the whole transcription-translation feedback loop to run its course through a single cycle. Biochemical reactions tend to happen at much shorter time scales. Some mathematical models tried to invent possible mechanisms (with no basis in experimental findings), while molecular biologists, in general, tended to ignore the problem altogether.
Still, I have seen in a few talks over the years some evidence that some circadian clock gene mutations affect only a portion of the cycle. In other words, if a mutation makes the endogenous period in a mutant shorter than that in a wild type, it is not because the whole cycle runs faster, but because one phase of the cycle runs faster. If I remember correctly from various talks, it was almost always the late-afternoon/early-evening phase that got affected.
Now, Young, Saez and Meyer published a paper in Science that sheds some light on the problem. In the process, they also significantly alter the model of the Drosophila circadian clock. You can see the old model in a movie here (see if you can play the movie directly by clicking on this), actually a series of movies produced a couple of years ago. You can see the new model here:
The big difference (let's completely ignore a dozen other molecular players for now) is in the behavior of two core clock proteins: PERIOD and TIMELESS. It was believed, until now, that it takes about six hours for the two proteins to find each other in the cytoplasm and that once they do, they bind to each other (heterodimerize), which is neccessary for their entry into the nucleus where they act to activate expression of some genes and supress expression of some other genes. No need for complicated details now.However, some very recent studies indicate that the two proteins break off from each other immediatelly before re-entering the nucleus, and they enter the nucleus alone, not as parts of a dimer.
What this new study does is demonstrate that the two proteins, as soon as they are formed, easily find each other and bind to each other, then sit idly in the cell for six hours before breaking off from each other and entering the nucleus. Also, mutations of Tim have no effect, while mutations of Per alter the duration the two proteins sit together as a dimer.
From the press release:
"They discovered that, rather than randomly colliding, the two proteins bind together in the cytoplasm almost immediately and create what Young and Meyer refer to as an "interval timer." Then, six hours after coming together, the complexes rapidly break apart and the proteins move into the nucleus singly, all of them within minutes of each other. "Some switch is thrown at six hours that lets the complex explode. The proteins pop apart and roll into the nucleus," Young says. "Somehow, implanted within the system is a timer, formed by Period and Timeless, that counts off six hours. You have a clock within a clock."Corpus Callosum comments:
What they found was that the interaction between the two proteins -- somewhat like the resonant frequency of a crystal, used as a timekeeper in an electronic circuit -- acts as a fundamental, but figurative, egg timer within a cell.It is possible that this is how it works.
One caveat though. The ability of the dimer to stay together for six hours, and the ability of the Per mutations to alter this timing, are not neccessarily the inherent property of the dimer. In other words, it may not have anything to do with resembling properties of a crystal.
They may just as well be the result of interactions between the dimer and other proteins in the cell, some of which may be influenced by the signalling coming from other cells (e.g., from neighboring pacemaker neurons).
In other words, the ability of the dimer to stay put for six hours may be a property of the dimer, or it may be a property of the multicellular system as whole.
posted by Bora Zivkovic at 1:39 AM
2 Comments:
That's a good point -- the behavior of the protein dimer is going to depend upon the cytoplasmic environment, which is subject to a wide variety of influences.
I tend to think that the egg-timer function is most likely intrisic to the interaction between the proteins in the dimer, because other factors, say the exact pH or the concentration of potassium or calcium ions, will vary, while presumably the periodicity of the timer does not.
Still, that is only an hypothesis. Obviously one would have to design a series of experiments to see if there are variables influence the periodicity. That's a lot of work, for a lot of hungry grad students.
I agree. That is one of the reasons this paper is so exciting.
It has a potential to put together all the molecular work with a whole series of studies that can be best described as "challenges" to the model, i.e., those that demonstrate that the nucleus as a whole, or some clock genes are not neccessary for overt circadian rhythmicity at the level of the tissue or organism.
I have to write a summary of those studies one day!
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