Cellular Navigation: Unravelling the Mysteries of Machines & Molecules

[cam875]

the more I think about it, the more I do not understand about cells and I've been trying to read as much as possible but I saw a video on youtube of cellular simulation showing some molecular machine moving on a molecular rope carrying a sack of proteins. So are there strands of rope networked all through the entire cell?

and how do specific molecules know exactly where to go to do there specific job, i mean everything seems so damn organized and efficient like a factory. Its obvious the molecules don't have garmin gps guiding them and its some sort of sensory system but can someone give me a little insight to how that actually works and why not all the molecules use ropes to move through nice networks.

 

[Ygggdrasil]

Yes. The cytoskeleton of a cell is made of "ropes" (actin), "cables" (microtubules), and other long chains of proteins. In addition to guiding transport in cells, they provide mechanical support for the cell and can have roles in cellular morphology (shape) and motion.

The molecular machines that you saw in the movie are referred to as motor proteins. There are three general classes of motor proteins: myosins, which move on actin fillaments, and kinesis and dyenins which move on microtubules. Interestingly, microtubules and actins both have a polarity to them; one end of the rope is different than the other end. This allows motor proteins to know which way they should move along these structures. In the case of microtubules, one end is referred to as the plus-end and the other is called the minus-end. Interestingly, a cell's microtubules are organized in such a way that the plus end is near the nucleus and the minus end is near the periphery of the cell (this comes about because microtubules grow preferentially from one end and growth is nucleated from structures around the nucleus).

As it turns out, kinesins move only toward the plus ends of microtubules and dyenins move only toward the minus ends of microtubules. Thus, one rough way by which the cell can target a cargo to a specific direction is by specifying the motor protein to which it associates.

After this level, things start to become less well understood. In some cases, proteins have "zip-code" tags that specify the correct location of the protein. Proteins which have the wrong zip code tags are exported from cellular structures while proteins with the correct tags are retained by the structure. In other cases, proteins associate with a particular location by binding to molecules that exist only at that location.

 

[Monique]

Interestingly, a cell's microtubules are organized in such a way that the plus end is near the nucleus and the minus end is near the periphery of the cell (this comes about because microtubules grow preferentially from one end and growth is nucleated from structures around the nucleus).

I think you have it the wrong way around. Microtubules are nucleated from MTOCs (microtubule organizing centers), which results in minus ends at the MTOC and plus ends at the cell cortex (although minus ends may also exist near the cell cortex).

 

[cam875]

wow, that's interesting, but how do enzymes and different things move in the right directions while just swimming in cytoplasm.

 

[Monique]

The motor proteins can carry cargo, by binding to either minus-end or plus-end directed motor proteins they can move around the cell. You can actually label the proteins with GFP and see them move along a microtubule.

 

[cam875]

so does everything get hooked onto something on a microtubule, instead of just randomly swimming? so if an enzyme needs to get to the other side of the cell, it will bind to a motor guy on a microtubule and he will help take him to the other side? or is there cases where the protein will just swim itself to the other side of the cell? sorry for all the questions and confusion but this is a new concept for me. Before in school I was just told that this does this and it will get to where it needs to go because it just does lol.

 

[Andy Resnick]

How proteins are trafficked is not fully understood yet. Certainly the elements are (reasonably) known, but the signalling cues are not- how do some membrane proteins get sent to the apical side, others to the basolateral side, for example.

I think the tag to send proteins into the nucleus is known, but I'm not sure how well understood nuclear trafficking is.

 

[Ygggdrasil]

I think you have it the wrong way around. Microtubules are nucleated from MTOCs (microtubule organizing centers), which results in minus ends at the MTOC and plus ends at the cell cortex (although minus ends may also exist near the cell cortex).

I indeed get it the wrong way around. Thanks for the correction.

I think the tag to send proteins into the nucleus is known, but I'm not sure how well understood nuclear trafficking is.

The mechanism of nuclear transport is fairly well understood. Basically, it's driven by a "Ran gradient." Ran is a small GTPase that can convert between a GTP bound form and a GDP bound form. I don't remember the specifics, but one side of the nuclear envelope has a GAP that will convert RanGTP to RanGDP and the other side will have a GEF to convert RanGDP to RanGTP. The different forms bind to different classes of cargo, so conversion from one form of Ran to another will cause a certain cargo to be released by Ran only on the correct side of the nuclear envelope.

Alberts Molecular Biology of the Cell will have a better explanation if you are interested.

 

[Monique]

How proteins are trafficked is not fully understood yet. Certainly the elements are (reasonably) known, but the signalling cues are not- how do some membrane proteins get sent to the apical side, others to the basolateral side, for example.

There is some extensive literature on the localization of proteins, the following is a nice review http://www.nature.com/nrm/journal/v9/n5/pdf/nrm2388.pdf

 

[cam875]

alright thanks for the info.

 

[Andy Resnick]

There is some extensive literature on the localization of proteins, the following is a nice review http://www.nature.com/nrm/journal/v9/n5/pdf/nrm2388.pdf

Is that what you meant to send? It is a review of (asymmetric) cell division, not cellular polarity. Looks interesting- I'll read it, for sure.

 

[Andy Resnick]

The mechanism of nuclear transport is fairly well understood. Basically, it's driven by a "Ran gradient." Ran is a small GTPase that can convert between a GTP bound form and a GDP bound form. I don't remember the specifics, but one side of the nuclear envelope has a GAP that will convert RanGTP to RanGDP and the other side will have a GEF to convert RanGDP to RanGTP. The different forms bind to different classes of cargo, so conversion from one form of Ran to another will cause a certain cargo to be released by Ran only on the correct side of the nuclear envelope.

Alberts Molecular Biology of the Cell will have a better explanation if you are interested.

I hear what you are saying, and I recall the Ran story, but I thought the nuclear pores are quite large and consitutively open- what prevents free diffusion of small molecules into and out of the pore?

 

[Monique]

Is that what you meant to send? It is a review of (asymmetric) cell division, not cellular polarity. Looks interesting- I'll read it, for sure.

You need polarity to divide asymmetrically you're right that this is a more specialized function, but it is a recent review and it covers multiple organisms.

 

[Ygggdrasil]

I hear what you are saying, and I recall the Ran story, but I thought the nuclear pores are quite large and consitutively open- what prevents free diffusion of small molecules into and out of the pore?

The answer to that question is not so clear yet. I'm not an expert in the field, but I remember reading an interesting paper that hypothesizes that certain unstructured regions of the peptides making up the NPC form a gel-like matrix that acts as a semi-permeable barrier. Only molecules with certain surface properties can be solvated in the gel and pass through. The citation to the paper is below:

Frey S, Görlich D. A Saturated FG-Repeat Hydrogel Can Reproduce the Permeability Properties of Nuclear Pore Complexes. Cell 2007 Aug 10;130(3):512-523. http://dx.doi.org/10.1016/j.cell.2007.06.024

 

[Andy Resnick]

You need polarity to divide asymmetrically you're right that this is a more specialized function, but it is a recent review and it covers multiple organisms.

Yes, but terminally differentiated epithelial and endothelial cells have a luminal side and a blood side; not only are membrane proteins segregated, but the membrane itself has different compositions. I don't know if anyone had argued that asymmetric cell division has any role or common players with terminal differentiation.

My point is simply that protein trafficking is poorly understood at the cellular level: how a cell is spatially organized.