December 2, 2007 | David F. Coppedge

Cell Gatekeepers: Diverse, Complex, Accurate

Cargo moves around rapidly and ceaselessly in every cell.  Some moves in and out of the external membrane, and some moves in and out of organelles and the nucleus.  In a system of protected domains surrounded by impermeable membranes, how does the cell control what should pass?  Details of the amazing gatekeeping mechanisms embedded in cell membranes have been coming to light for years now.  Some recent articles have reported the latest findings. 

  1. Protective sleeve:  One method of getting valid cargo through the membrane gate is to wrap it in a protective sleeve that the gate recognizes.  PhysOrg has an illustration from the work of a team at Purdue showing how this works.  What comes to mind is a personal subway capsule that shuttles you to an escalator that transfers you safely into a shopping mall without any intruders getting past.
  2. Electronic gating:  Ions are electrically-charged atoms whose concentration in the cell must be strictly controlled.  Compared to the large molecules of the cell, ions of potassium, chlorine and sodium are tiny.  Special voltage-sensing gates exist just for them.  We reported here on early results from work by Roderick MacKinnon into the structure and function of these ionic gates (see 01/17/2002, 05/29/2002, 05/01/2003, 08/05/2005).
        The November issue of The Scientist describes ongoing discoveries about one of these voltage-gated channels, the Kv potassium channel.  This electronic mechanism contains a pore, a gate and a voltage sensor.  In particular, a key helix protein component called S4 undergoes a conformational change to open the gate for the potassium ion.  People who enjoy exercise may want to reflect that all nerve and muscle activity depends on the proper control of these ions.
  3. Nuclear power plant security:  For those wanting to follow up on news about the nucleus, and how it controls the cargo going in and out (see last month’s entry, 11/13/2007, bullet #2), the crew of your nuclear power plant made the cover of Science this week.  Laura Trinkle-Mulcahy and Angus I. Lamond reviewed the latest work to get high-resolution images of the complex structures and functions of the nuclear membrane, especially the gates of the nuclear pore complex (NPC).1
        Four other articles in the 11/30 issue describe the latest findings about the cell nucleus.  A paper by 3 Vanderbilt University scientists specifically addresses the factors involved in crossing the nuclear envelope through the NPC gates.2  For those wanting more information about the sensing mechanism, their article contained color diagrams of the structures.  The scientists explained how the gates are regulated at multiple levels – a philosophy common in national security and computer security, too.  The “dynamic and diverse” mechanisms control what passes at the gate level, the transport receptor level, and the cargo level.  In computer parlance, this might be analogous to requiring a fingerprint, a secure computer, and secure software before you are allowed to login.
        Another paper in the same issue of Science describes science’s growing realization that the nuclear membrane does far more than let things in and out.3  It is actively involved in cell division, structuring the cytoskeleton, and signaling other processes in the cell.  The nuclear envelope is also connected to the endoplasmic reticulum, a structure essential for post-translational modification of proteins.  The authors did not mention how these elaborate mechanisms might have evolved, except to say twice that they raise “intriguing questions” and “fundamental questions” about “evolutionary relations” between the parts.  The other two papers did not mention evolution at all.
  4. ER: emergency room or endoplasmic reticulum:  Speaking of the endoplasmic reticulum (a kind of subway system within the cell), Nature reported studies about the transport channels in that organelle.4  “A decisive step in the biosynthesis of many proteins is their partial or complete translocation across the eukaryotic endoplasmic reticulum membrane or the prokaryotic plasma membrane,” began Tom Rapoport (Howard Hughes Medical Institute, Harvard).  “Most of these proteins are translocated through a protein-conducting channel that is formed by a conserved, heterotrimeric membrane-protein complex, the Sec61 or SecY complex.”
        Polypeptides are the pre-protein strings of amino acids emerging from ribosomes, where the translation from RNA occurs.  Getting a wobbly chain of molecules through a pore is somewhat akin to threading a needle.  Depending on what the cargo binds to, it may get in by one of several ways: the ribosome may simply attach to and inject the nascent polypeptide into the channel, an ER chaperone might pump it in by a ratcheting mechanism, or a molecular machine running on ATP might push the polypeptide through.  These are all regulated by a host of assisting proteins that keep in touch through signaling mechanisms.  There’s even a plug that closes the channel after the polypeptide is inside.
        Rapoport provided a diagram of the complicated-looking translocation channel, which is made up of three different protein parts.  He called it conserved (unevolved) between all three kingdoms of life, but did not say anything else about evolution – certainly, not anything about how it arose in the first place.
  5. Light sensitive:  Imagine a receptor on a cell membrane that can respond to one photon of light, and send a signal into the interior.  You don’t have to imagine it: it already exists.  Rama Ranganathan in Science described the family of G-protein coupled receptors (GPCR) that “occur in nearly every eukaryotic cell and can sense photons, cations, small molecules, peptides, and proteins.”5  How do they do it?  The structures of these receptors are just beginning to come to light, and basic models are being formulated.  Stay tuned.

Most of the articles above said nothing about how these complex transportation systems might have evolved.  A review in Nature,6 however, proposed that “the plethora of transport factors found in modern eukaryotes may have also evolved by duplication events, keeping pace with the evolutionary duplication and diverging specialization of the FG nucleoporins in the NPC’s [nuclear pore complex’s] modules.”  Noting some similarities in the NPC to clathrin-coated endocytosis, the team of a dozen UK and American scientists suggested that gene duplication was the method of evolution: “the NPC is another example of how a complicated structure can evolve from the duplication, divergence and elaboration of simple ancestral modules,” they claimed.  They also downplayed the complexity of the NPC by pointing out some of the proteins are used in a modular fashion.  A summary and diagram was posted by PhysOrg.
    Their evolutionary explanation, however, was based entirely on circumstantial evidence of similarity, not on a chain of plausible steps for how diverse mechanisms, despite some structural similarities, achieved their high levels of functional accuracy.

1.  Laura Trinkle-Mulcahy and Angus I. Lamond, “Toward a High-Resolution View of Nuclear Dynamics,” Science, 30 November 2007: Vol. 318. no. 5855, pp. 1402-1407, DOI: 10.1126/science.1142033.
2.  Laura J. Terry, Eric B. Shows, Susan R. Wente, “Crossing the Nuclear Envelope: Hierarchical Regulation of Nucleocytoplasmic Transport,” Science, 30 November 2007: Vol. 318. no. 5855, pp. 1412-1416, DOI: 10.1126/science.1142204.
3.  Colin L. Stewart, Kyle J. Roux, Brian Burke, “Blurring the Boundary: The Nuclear Envelope Extends Its Reach,” Science, 30 November 2007: Vol. 318. no. 5855, pp. 1408-1412, DOI: 10.1126/science.1142034.
4.  Tom O. Rapoport, “Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes,” Nature 450, 663-669 (29 November 2007) | doi:10.1038/nature06384.
5.  Rama Ranganathan, “Signaling Across the Cell Membrane,” Science, 23 November 2007: Vol. 318. no. 5854, pp. 1253-1254, DOI: 10.1126/science.1151656.
6.  Alber et al, “The molecular architecture of the nuclear pore complex,” Nature 450, 695-701 (29 November 2007) | doi:10.1038/nature06405.

The evolutionary speculations in Nature provided nothing to the real scientific work in these papers.  They did not help determine the structure, function or dynamics of any of the transport mechanisms.  They were mere after-the-fact pipe dreams about how Charlie might be vindicated with a hefty dose of LSD (Let’s Support Darwin).
    Gene duplication is pitifully incapable of explaining how functional information got into either clathrin-coated endocytosis or nuclear pore transport.  A motorcycle and a diesel train have some similarities, too; they both have wheels that rotate and are powered by fuels that have some similarities (hydrocarbons).  So what?  You can duplicate as many motorcycles as you want, for eternity, and will never get a bullet train.  Even if you allow the duplicate motorcycle unlimited free mutations, will that help?  Try breaking things at random on the motorcycle and see if you make progress toward train technology.  Darwinian evolution is blind, remember.  It has no foresight.  It is not trying to work toward traindom.  Unless each mistake provides some advantage for the here and now, the only likely result is that repeated mutations will leave you stranded on the highway bumming a ride.
    Sorry we had to waste time on evolution.  The focus of this story should be on the amazing mechanisms of the cell, and how modern science is slowly pulling back the cover on the package so we can all, with the fascination of kids at Christmas, look inside and see the words LION-EL.*

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