Cells Perform Sporting Interactions

The components of living cells perform such acrobatic moving interactions, one would think they are having fun.  Here’s the news from the Wide World of Cellular Sports.

1. Speedway:  A news release from Penn Medicine talks about how motor proteins step on the gas and the brakes in their motions around the cell.  The announcer from the booth calls the action:
   

   “Imagine that the daughter microtubule is a short train on the track of the mother microtubule,” explains [Phong] Tran.  “The molecular motor is the train’s engine, but the problem is that the cargo – the molecular brakes – gets longer, slowing down the daughter train.  But when the train gets to the end of the track it remains attached to the end of mother microtubule.  At the tail end, it stops moving and that defines the region of overlap.  Our work shows that the cell can make microtubule structures of defined lengths stable by coordinating the sliding of the motors and the slowing of the brakes.”

   The press release contains videos of the speedway in action.

2. Square Dance:  Chromosomes line up in their territories like square dancers on cue, explained an article in Nature (1/25).¹  They even use their arms: “In addition, the structure of the DNA within chromosome territories is nonrandom, as the chromosome arms are mostly kept apart from each other and gene-rich chromosome regions are separated from gene-poor regions.  This arrangement probably contributes to the structural organization of the chromosome, and might also help in regulating particular sets of genes in a coordinated manner.”
       “Remarkably,” even the territories themselves “arranged in particular patterns within the nucleus,” the article explains.  Here’s part of the choreography inside the dance hall (i.e., the nucleus):

   In lower eukaryotes such as plants and flies chromosomes tend to be polarized, with the ends of the arms (telomeres) on one side of the cell nucleus and the point at which the two arms meet (the centromere) on the opposite side.  In mammalian cells, however, chromosome arrangement is more complex.  Even so, each chromosome can be assigned a preferential position relative to the nuclear centre, with particular chromosomes tending to be at the nuclear interior and others at the edge (Fig.  2a).  This preferential radial arrangement also, of course, gives rise to preferred clusters of neighbouring chromosomes.
   

   The players get to socialize, too: “Even the two copies of the same chromosome within the same nucleus often occupy distinct positions and have different immediate neighbours.”  Each chromosome tends to hang out with partners in the same developmental pathways, though.  “It seems that the actual position of a gene in the cell nucleus is not essential to its function,” the author writes.  So, the interviewer asks, “Why have all this organization?”  Is it just for fun?  “It is more likely that positioning contributes to optimizing gene activity.”  It also serves the time-honored strategy of networking:

   The nonrandom organization of the genome allows functional compartmentalization of the nuclear space.  At the simplest level, active and inactive genome regions can be separated from each other, possibly to enhance the efficiency of gene expression or repression.  Such compartmentalization might also act in more subtle ways to bring co-regulated genes into physical proximity to coordinate their activities.  For instance, in eukaryotes, the genes encoding ribosomal RNAs tend to cluster together in an organelle inside the nucleus known as the nucleolus.  In addition, observations made in blood cells suggest that during differentiation co-regulated genes are recruited to shared regions of gene expression upon activation.

   How each partner finds its spot, we don’t know.  Somehow, they always find their way back: “Chromosomes are physically separated during cell division, but they tend to settle back into similar relative positions in the daughter cells, and then they remain stable throughout most of the cell cycle.”  The author claims this behavior is “evolutionarily conserved” (i.e., unevolved).

3. Baton race:  Passing chemical tags without stumbling is described by a paper in Nature² that opens, “Modifier proteins, such as ubiquitin, are passed sequentially between trios of enzymes, like batons in a relay race.  Crystal structures suggest the mechanism of transfer between the first two enzymes.”  As the tags get passed from group to group, the players sometimes undergo large shape changes to hold the tag properly.  In one case, for instance, “combined conformational changes create a surface to which an E2 enzyme binds with high affinity.”  These bends and rotations make the enzymes act like a “conformational switch” to turn on the next reaction in the chain, like handing off the baton.
4. Capture the Flag:  Another paper in Nature³ described how the cell cycle often depends on reading tags hidden on chromosomes.  Describing the “intricate process” of this game, even describing the participants as “players,” a researcher from UC Berkeley calls the action: “Transitions between all cell-cycle phases are controlled by the activation and deactivation of a series of cyclin-dependent kinases (CDKs), which control the phosphorylation of other proteins.”  Researchers were having a challenge following the flag.  “Thus, after the origin-recognition complex had been identified, finding the actual targets for S-CDK, the CDK known to promote the switch from G1 to S phase, became a major objective.”
5. Acrobatics and juggling:  A paper in PNAS⁴ describes the dynamic motions of one enzyme that uses three metal ions and multiple conformational changes for precise action on its substrate.  “It is evident that the trimetal cluster undergoes significant structural reorganization in the course of the reaction,” they wrote.  Visualize this circus act as they describe it:
   

   The analysis presented here emphasizes the significant level of complexity involved in enzymatic catalysis by multinuclear enzymes even when the underlying chemical transformation is relatively straightforward.  At the same time certain universal patterns regarding the multiple mechanistic roles of the metal cofactors emerge.  First, the metal ions play a role in generating the reactive nucleophile.  This process involves precise positioning of a carboxylate ligand to deprotonate an exogenous water molecule and orient the resulting hydroxide for an in-line attack.  Deprotonation is further facilitated by the combined electrostatic effect of two zinc ions (Zn1 and Zn2), necessitating a relatively close distance between them.  The second role of the metals is to accommodate and electrostatically stabilize the more compact partly associative transition state.  Hence, an overall contraction of the trimetal cluster is observed.  Finally, a metal cofactor (Zn3) is responsible for stabilizing the developing charge on the leaving group toward the end of the reaction.  To effectively carry out these roles, the active site rearranges dynamically, a finding, that underscores the crucial importance of flexibility for the reactive transition.

   Since this enzyme is part of the DNA Repair Team, the participants probably don’t do it for applause or to be heroes.  To them, it’s all in a day’s work.

Human researchers seem to be joining in the games.  Identifying the sports repertoire inside a cell is like a treasure hunt.

¹Meaburn and Misteli, “ Nature 445, 379-781 (25 January 2007) | doi:10.1038/445379a.
²Trempe and Endicott, “Structural biology: Pass the protein,” Nature 445, 375-376 (25 January 2007) | doi:10.1038/nature05564.
³Michael Botchan, “Cell biology: A switch for S phase,” Nature 445, 272-274 (18 January 2007) | doi:10.1038/445272a.
⁴Ivanov, Tainer and McCannon, “Unraveling the three-metal-ion catalytic mechanism of the DNA repair enzyme endonuclease IV.” Proceedings of the National Academy of Sciences USA, doi 10.1073/pnas.0603468104, January 30, 2007, 104:5, pp. 1465-1470.

We used to think of chemistry as bonding of outer electrons in orbitals as molecules bounce against each other at random.  Biochemistry has shown much of the action in cells to be mechanical in nature, with parts acting like machines, dancers and acrobats.  It’s hard not to view this new living chemistry as a series of sporting events by highly skilled players.  Be sure to cheer for your home team.