November 15, 2008 | David F. Coppedge

Cell Chaperone Is an Optimized Two-Stroke Machine

Proteins need a protected space to fold, and the cell provides it: the GroEL-GroES chaperone (see 05/05/2003, 06/07/2006, and 02/13/2007).  More details keep coming in about this “protein dressing room” as scientists continue to probe its secrets.  Two new papers in PNAS by a team at University of Maryland and College Park reveal that this is no passive cavity.  The system acts like a two-stroke engine with two timers.1,2 
    John P. Grason et al have examined the machinery in action, and found truly amazing properties in this tiny but complicated system.  We’ll try here to reduce their complex jargon into easily-pictured analogies.  To picture GroEL, think of two donut-shaped rings, studded with electronics, that stack on top of one another.  We’ll call them cis and trans.  The cis ring on the bottom has a floor, while the trans ring is open.  When stacked, they form a barrel-shaped cavity.  On top, another protein called GroES fastens and forms a protective cap.  Now we have something like a scuba diver’s emergency decompression chamber, if you can picture it.
    A good decompression chamber is going to keep the patient inside long enough, but not too long.  Humans can control their chambers, but how does a sightless nanomachine do it?  The answer: through the use of timers.  There are two timers in the GroEL-GroES system that operate independently.  Working together, they optimize the time the protein inside has for folding, without letting the prima donna hog the dressing room when others need to use it (sorry for the mixed metaphors).  How the system accomplishes this is truly astonishing.
    Deploying ATP energy, the two rings twist back and forth against each other, creating strain.  They undergo a two-stroke cycle: starting in phase, then twisting 180° with respect to each other, then back again.  The authors call the stages taut (T) and relaxed (R); when cis is taut, trans is relaxed, and vice versa.  Their two-stroke cycle time is dependent on the protein inside the barrel and on the presence of ATP and potassium ion.  This gives the operation some flexibility.  The protein in the dressing room isn’t unnecessarily rushed, and the chamber isn’t wasting energy when no one is inside.  The other timer, though, is like a countdown timer with no mercy.  In the floor of the cis ring, a second timer running on ATP has a time limit that starts when the lid closes.  When the timer hits zero, the protein is booted out, folded or not (see footnote 3).
    Working together, these two timers optimize the protein folding time.  The variable timer, like an idling engine, goes to work when the protein enters.  It tries to adjust its time to the needs of the protein inside.  But if the protein doesn’t finish folding in the 3-to-4 second window of the second timer, it gets ejected.  It can, however, come back in for a second try.  The protein can keep trying, in fact, till it succeeds or gives up and gets recycled by the trash collection process (a “very sophisticated recycling system” described this week on PhysOrg).  Here’s how the authors describe how the timers interact:

In the absence of SP [substrate protein inside the cavity], the chaperonin machine idles in the resting state, but in the presence of SP it operates close to the speed limit, set by the rate of ATP hydrolysis by the cis ring.  Thus, the conformational states [i.e., twisting motions] of the trans ring largely control the speed of the complete chaperonin cycle.

What this means is that every actor gets a shot at the dressing room, but those with more costuming and make-up (i.e., more complex proteins) get more time – within limits.  If it exceeds the upper limit it has to go back outside and wait for another turn.  The authors called this flexible mechanism, which coordinates a variable timer with a non-variable timer, “iterative annealing.”  They said iterative annealing is “simply a biological example of a well known and widely used principle of optimization.”  Maybe public shower operators could learn something here.
    Analogies have their limitations, but to show that we are not making this up, here is the summary explanation in their own words.  Look for a hint of excitement in their discovery:

The picture of the chaperonins that emerges from our work is that of a machine equipped with a timer, the trans ring, poised to respond to the appearance of SP [substrate protein inside the cavity] but otherwise idling in a quiescent state.  We note that Nature’s design of this 2-speed protein machine minimizes the hydrolysis of ATP in the absence of SP.  However, it maximizes the number of turnovers and minimizes the residence time available to the encapsulated SP to reach the native state, design principles well suited to the operation of an iterative annealing device.

How did this system arise?  One of the papers began with an oblique reference to evolution that raises more questions than it answers: “As with many other cellular machines, the chaperonin nanomachine has evolved to operate at variable speed in response to biological demand.”  This puzzling statement seems to imply teleology – a sin in the world of Darwinian explanations.  In neither paper, however, did the authors speculate on how a blind, purposeless process could have produced an optimized system as functionally efficient and complicated as the GroEL-GroES chaperone.  Quite the contrary.  The quote above used the word Design twice.
Note: Both papers are categorized as Open Access and can be read in their entirety online; see footnotes.

1.  Grason, Gresham, Widjaja, Wehri and Lorimer, “Setting the chaperonin timer: The effects of K+ and substrate protein on ATP hydrolysis, Proceedings of the National Academy of Sciences USA, published online before print November 6, 2008, doi: 10.1073/pnas.0807429105 (open access article).
2.  Grason, Gresham and Lorimer, “Setting the chaperonin timer: A two-stroke, two-speed, protein machine,” Proceedings of the National Academy of Sciences USA, published online before print November 6, 2008, doi: 10.1073/pnas.0807418105 (open access article).
3.  The famous adventurer John Muir as young man invented a bed that would raise up when the alarm went off, putting the surprised sleeper on his feet.

Don’t get too mad at Dr. Grason for putting the E-word into the paper.  If he hadn’t paid homage to Charlie’s Totalitarian Regime, he might have been Expelled.  At least there is progress: the D-word outscored the E-word two to one.  What a great day it will be when scientists are free to express joy at the designs they explore without having to say stupid things like “it evolved” (05/25/2005 commentary).

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