As with any complex city or factory, transportation is a key function. It’s been awhile since we discussed the cellular railroad, so let’s refresh our memory about the trains and tracks in cellular transportation systems with this summary from an article on Phys.org:

Using an analogy to a metropolitan city, the interior of eukaryotic cells contain a railway-like structure called the cytoskeleton and tiny vehicles called motor proteins. Motor proteins act on the cytoskeleton tracks to generate forces and directional movement for many essential processes, such as transportation of cellular “cargoes” and separation of duplicated chromosomes during cell division.

Cells from human, animals and fungi all have three different types of motor proteins that scientists refer to as myosin, kinesin and dynein. Kinesin and dynein move on the same cytoskeleton track and normally in opposite directions. [Emphasis added.]

Myosin moves on a different railway called the actin network. So there you have it: three engines on two kinds of tracks. Notice that they really are machines, generating forces and moving things around. Before looking at the news, it might be worthwhile to review our animation of kinesin, the workhorse of the cell.

Tugging Engines

Another article on Phys.org discusses new discoveries about muscle cells. Preliminary cells called myocytes join together into muscle fibers (myotubes), causing the completed fibers to have multiple nuclei. Those nuclei, as patients with muscular dystrophy and other tragic diseases find out, must be accurately placed for skeletal muscles to work. Do the nuclei just happen to drift into the right place? Certainly not! Chance and natural law can’t be trusted for such a vital function. The nuclei must be pulled into position by the intracellular railroad of microtubules and kinesin engines. A host of proteins and regulators position the microtubule tracks onto the nuclear envelope so that the kinesin engines will pull in the right direction. The open-access paper in Current Biology tells how this works:

Correct nuclear positioning is important for muscle function, and mislocalized nuclei are often associated with muscular diseases. The MT [microtubule] network, MT motor proteins, and MT-associated proteins (MAPs) have been implicated in nuclear positioning during skeletal muscle formation. Furthermore, Nesprin-1 was reported to be involved in the distribution of skeletal muscle nuclei through the recruitment of kinesin-1 motor proteins to the NE [nuclear envelope] in vivo and in vitro. However, it is unknown whether MT nucleation from the NE is also important for nuclear positioning…. These results strongly support the hypothesis that Nesprin-1-mediated MT nucleation from the NE via Akap450 is required for nuclear positioning in myotubes.

Without these two essential proteins, the microtubules fall apart, debilitating the muscle cell. Incidentally, the authors found 446 proteins that associate with one of the Nesprin-1 isoforms. Remember how improbable it is to get one protein by chance? (For a refresher, see Doug Axe’s book Undeniable, or watch the clip “Amoeba’s Journey” from Origin by Illustra Media.)

This is a remarkable example of hierarchical design with physics. To the physiologist, muscle fibers need proper attachment to bone for a bicep to generate the correct force. To a microbiologist — working at a scale orders of magnitude smaller — microtubules need proper attachment to the nuclear envelope for kinesin to generate the correct force. Does Nesprin-1 “know” that its regulation of microtubule attachment is necessary for the higher-order muscle to work? Of course not; these two force-generating systems are oblivious to each other, but both are essential for a military recruit to be able to do pull-ups in boot camp. Fascinating!

Plant Design Principles

The Phys.org article first mentioned goes on to discuss a particular member of the kinesin family in plants called kinesin-14. It begins with mixed messages about “design principles” and evolution:

A research team led by an Oregon State University biophysicist and a plant biologist from University of California, Davis has discovered a novel motor protein that significantly expands current understanding of the evolution and design principle of motor proteins.

Kinesin-14 and dynein have the same directional preference on microtubules, but in animals and fungi, this particular motor protein can’t stay on track for long. Because plants lack dynein, the biologists assume that plants compensated for the lack of dynein by “evolving” a special form of kinesin-14 with persistent motion on microtubules. They repeat the mixed messages:

“This expands our knowledge of the design and operation principles of molecular motors,” he [Weihong Qiu of OSU] said. “Land plants offer a rich source for us to understand the entire evolution of these molecular motors. And some land plants, if not all, have evolved novel kinesin-14 motors to potentially compensate for the loss of dynein.”

The mixed messages about “design principles” and evolution continue in the open-access paper in Nature Communications.

Collectively, our results not only show that land plants have evolved unconventional kinesin-14 motors with intrinsic minus-end-directed processivity, but also markedly advance current knowledge of the design principles of kinesin-14s.

Elsewhere in the paper, though, the eight co-authors admit that the evolutionary hypothesis is only an idea that “has long been speculated” by researchers. Nowhere do they mention natural selection, phylogeny, or ancestry. Design principles are open to observation; an evolutionary prehistory is not. Thankfully, most of the paper consists of observational evidence for the design principles of these kinesins that “may function in vivo to control nuclear positioning.” At best, the “evolution” regards a particular form of kinesin-14 that can cling to the microtubule on its own for longer distances than others that work in clusters — a modest change in this one form that appears to be due to loss of a particular coiled-coil flanking domain.

Rush Hours and Brakemen

A much more design-friendly article from Washington University in St. Louis extols the efficiency of the molecular railroad. Like the above article, it focuses attention on kinesins in plants, this time kinesin-4, a form responsible for depositing material on the cell wall. For this function, time regulation is essential:

“Similar to rush hours, when plants are rapidly growing, you need to deliver a lot of cell wall material to keep up with growth,” Ganguly said. “Efficient, high-volume transport depends on having a lot of motor proteins. The regulator we discovered keeps a surplus of these transporter proteins around during times of rapid growth.”

Just as important, though is the ability to halt the motors when they reach their destination, and regulate their unloading. Fortuitously, a molecular brakeman is on duty. Called IMB4, it “holds the kinesin in an inactive state — protecting it from degrading while it waits — and prevents the kinesin from traveling along a microtubule until its cargo is needed.” By binding to the kinesin-4, IMB4 “jams” the motor like applying a parking brake. Design advocates will enjoy the opening analogy in this Darwin-free news item:

Within both plant and animal cells, motor proteins act like the engines in a busy train system. They shuttle material in the cell from one location to another. And just as commuter trains travel a predictable route in a defined direction, their volume of transport is commensurate with need. At rush hour, more trains are in operation. At midnight, there’s no point in running trains every 10 minutes.

In a growing plant cell, motor proteins called kinesins work as transporters that haul materials built in one part of the cell to the place where they are needed. Kinesins travel along tracks of polymers known as microtubules to get where they are going. Moving cargo costs the cell energy and resources, and this process is closely controlled to prevent waste.

Detail freaks can learn more in the paper in Developmental Cell.

Self-Adjusting Railroads

The heroic efforts to build America’s railroads make for great stories of dedication and sacrifice. One limitation of human railroads, however, is that once the tracks are laid, it’s very difficult to change them. Here’s an advantage cellular railroads have, as described more Darwin-free news from the University of Warwick, where Professor Robert Cross found something amazing:

Almost every cell in our bodies contains a ‘railway’ network, a system of tiny tracks called microtubules that link important destinations inside the cell. Professor Cross’ team found the system of microtubule rails inside cells can adjust its own stability depending on whether it is being used or not.

Prof Cross said: “The microtubule tracks of the cellular railway are almost unimaginably small — just 25 nanometres across (a nanometre being a millionth of a millimetre).The railway is just as crucial to a well-run cell as a full-size railway is to a well-run country. For cells and for countries the problem is very much the same — how to run a better railway?”

“Imagine if the tracks of a real railway were able to ask themselves, ‘am I useful?’ To find out, they would check how often a railway engine passed along them.

“It turns out that the microtubule railway tracks inside cells can do exactly that – they check whether or not they are in contact with tiny railway engines (called kinesins). If they are, then they remain stably in place. If they are not, they disassemble themselves. We think this allows the sections of microtubule rail to be recycled to build new and more useful rails elsewhere in the cell.”

The way it works is also fascinating: “when the kinesin railway engines contact their microtubule rails, they subtly change their structure, producing a very slight lengthening that stabilises the rail.” This 1.6 percent increase in the microtubule length confers a 200-fold lifetime on the trackway, Cross found.

Because microtubule defects are implicated in some cancers and brain disorders, understanding the design may lead to new treatments. It also sounds like a nifty way to build a self-stabilizing railroad network. Follow the example of the “microscopic ‘railway’ system in our cells [that] can optimise its structure to better suit bodies’ needs.” Elon Musk, are you listening?

Photo: Washington University researchers extol the efficiency of the molecular railroad, by Joe Angeles.