September 3, 2009 | David F. Coppedge

Molecular Machines on Parade

Scientific papers continue to exhibit the exquisite mechanisms in the cell for handling all kinds of situations, through the operation of molecular machines.  Here are a few recent examples from this week’s issue of Nature (Sept 3, 2009).

  1. Molecular sieve:  What happens when a cell gets bloated?  Too much water entering a cell can increase the pressure against the membrane, “potentially compromising the integrity of the cell,” said Valeria V�squez and Eduardo Perozo in Nature this week.1  They described findings about a molecular sieve named MscL by Liu et al in the same issue of Nature.2  MscL in bacteria is made up of multiple protein parts that form a pore in the cell membrane.  The research team from Caltech and Howard Hughes Medical Institute found that the components flatten out and pivot, opening up the pore like an iris when sufficient pressure is applied.  This is called “mechanosensation” because it operates automatically via mechanical pressure.  “These channels act as ‘emergency relief valves,’ protecting bacteria from lysis [disruption] upon acute osmotic down-shock,” the authors said.  “MscL has a complex gating behaviour; it exhibits several intermediates between the closed and open states, including one putative non-conductive expanded state and at least three sub-conducting states.”  The team’s contribution was to image one of the intermediate states.
        The research paper did not mention evolution.  V�squez and Perozo, however, said, “free-living cells have evolved a variety of mechanisms to deal with sudden variations in the physicochemical properties of their surroundings,” and later said, “Most prokaryotes (bacteria and archaea) have therefore evolved a ‘pressure-release valve’ mechanism in which changes in membrane tension open up channels to form large, aqueous pores in the membrane,” but they did not explain how evolution could have accomplished this.  They made it sound like the bacteria purposely employed evolution (whatever they meant by the term) to solve a real problem.  They did not explain how bacteria got through osmotic down-shock without the pressure release valves.
  2. Molecular taxicab:  Transfer RNAs (tRNA) are made in the nucleus but need to commute to work outside, in the cytoplasm, where the ribosomes are.  They are small enough to barely squeeze through the nuclear pore complex (NPC) – the complicated gates in the nuclear membrane that control traffic in and out – but they don’t avail themselves of that freedom, lest their exposed parts interact with the authentication mechanisms of the NPC.  Instead, they hale a taxicab to escort them through.  That taxicab, or “tRNA export factor,” is called Xpot.
        Xpot is a complex molecule that fits around the exposed parts of the tRNA.  It literally “wraps around” the tRNA, undergoing conformational changes as it clamps on.  Imagine a taxicab wrapping around you, and you get the picture.  Xpot is general enough to fit all 20 kinds of tRNAs, but specific enough to protect their delicate active sites.  It is also able to recognize and reject tRNAs that are immature.  Only tRNAs that have passed a processing exam are allowed in the taxi.  The authors of a paper in Nature who studied Xpot said, “Xpot undergoes a large conformational change on binding cargo, wrapping around the tRNA and, in particular, binding to the tRNA 5′ and 3′ ends.  The binding mode explains how Xpot can recognize all mature tRNAs in the cell and yet distinguish them from those that have not been properly processed, thus coupling tRNA export to quality control.3  As an additional control, Xpot does not interact with tRNA except in the presence of another factor in the nucleus called RanGTP.  After safe transport through the nuclear pore complex, another factor in the cytoplasm unlocks the RanGTP, allowing the Xpot taxicab to unwrap from the tRNA.  The tRNA then heads off to the ribosome to fulfill its work shift as a scribe, translating the genetic code into the protein code.  “Transfer RNAs are among the most ubiquitous molecules in cells,” they said, “central to decoding information from messenger RNAs on translating ribosomes.”
        The authors of the paper did not discuss how Xpot originated, but six times they said that parts of Xpot are either “conserved,” “evolutionarily conserved” or “highly conserved” (i.e., unevolved) throughout the living world.
  3. Molecular sherpa:  Kinesin is among the most fascinating molecular machines in the cell, because it literally “walks” hand-over-hand on microtubule trails, carrying cargo.  In doing this, it converts chemical energy from ATP into mechanical work.  Writing in this week’s Nature,4 Guydosh and Block of Stanford described direct observation of the binding state of the hands (called heads) of kinesin to the microtubule.  They found that it walks tiptoe on the tightrope: “Here we report the development of a single-molecule assay that can directly report head binding in a walking kinesin molecule, and show that only a single head is bound to the microtubule between steps at low ATP concentrations.”  The rear head has to unbind before the forward head can bind.  This keeps the kinesin from getting stuck with both feet (heads) on the tightrope.  If you can stand some jargon, here is what they said about the complexities of how this works:

    The inability of one head to bind the microtubule offers a natural explanation for the observation that the microtubule-stimulated release of ADP is inhibited until the microtubule-attached head binds ATP and docks its neck linker (Fig. 4, state 2).  Strain produced by an unfavourable neck-linker conformation also explains the observation that ATP does not bind prematurely to the front, nucleotide-free head of a 2-HB kinesin molecule (Fig. 4, state 3).  Any tight binding of ATP is disfavoured because it is coupled to neck-linker docking and, therefore, to the generation of a strained configuration in which both neck linkers are docked (Fig. 4, S3).  We anticipate that the single-molecule techniques presented here will be applicable to the study of dynamic properties of other motors and macromolecules that undergo analogous conformational rearrangements.

The fact that protein machines use energy to undergo conformational rearrangements, and that these “moving parts” perform functional work, places them squarely in the realm of machinery – except on a scale so tiny, their operations are only now coming to light.

1.  Valeria V�squez and Eduardo Perozo, “Structural Biology: A channel with a twist,” Nature 461, 47-49 (3 September 2009) | doi:10.1038/461047a.
2.  Liu, Gandhi and Rees, “Structure of a tetrameric MscL in an expanded intermediate state,” Nature 461, 120-124 (3 September 2009) | doi:10.1038/nature08277.
3.  Cook, Fukuhara, Jinek and Conti, “Structures of the tRNA export factor in the nuclear and cytosolic states,” Nature 461, 60-65 (3 September 2009) | doi:10.1038/nature08394.
4.  Guydosh and Block, “Direct observation of the binding state of the kinesin head to the microtubule,” Nature 461, 125-128 (3 September 2009) | doi:10.1038/nature08259.

Molecular machines – the very concept is only a couple of decades old.  This is phenomenal.  It is marvelous and wonderful beyond description.  You can almost sense the astonishment and excitement of these biophysicists uncovering these tiny wonders in the cell.  Who could have imagined this is how life works?  Think of the centuries, the millennia, of people going about their business, oblivious to the fact that at scales too tiny to imagine a whole factory of automated molecular machines was keeping them alive.  The few thinkers after the discovery of cells by Robert Hooke envisioned little people (homunculi) doing some of it, but our instruments were too coarse to elucidate the workings inside till recently – till our generation.  Next to the discovery of DNA and the genetic code this must be considered one of the most important discoveries in the history of science.  If Antony van Leeuwenhoek was astonished at what he saw with his primitive hand lens, how much more should we be flabbergasted at what is coming into focus, now that we can discern the activity of individual molecules?
    The Darwinists are strangely silent about all this.  In our 9 years of reporting, very few papers on molecular machines have even mentioned evolution (e.g., 10/02/2001, 01/09/2002), and those that did usually just assumed it rather than tried to seriously explain how the most primitive life-forms could have became endowed with factories of mechanical filters, scribes, taxicabs and walking robots by chance (e.g., 09/16/2000, 08/24/2009 08/26/2005).  Search on “molecular machines” in the search bar above and check.  There are lots of examples.  It’s time to cast off that antiquated 19th-century mindset that tried to imagine all this from the bottom up.  Let us regard as silly the tales of miracles of “emergence” occurring mindlessly in “a chance Motion of I don’t know what little Particles,” as Christiaan Huygens, our Scientist of the Month, quipped.  Paley is back with a vengeance.  The contrivances of nature are more wonderful than he or any other philosopher or scientist could have imagined.  It’s a Designed world after all.  Rejoice, give thanks and sing!

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