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The question might be asked for any kind of "bound" proteins, but I'd like to restrict it to membrane proteins.

Assuming membrane proteins (or their main parts) don't (or aren't) build in situ but at some distance of the membrane, I wonder by which mechanisms they travel from their generation site to their final destination inside the membrane (inner or outer).

Proteins that are distributed roughly evenly (or randomly) over the membrane don't pose a big conceptual problem: they could have gone their just by diffusion, possibly from many generation sites, distributed roughly evenly (or randomly) inside the cell.

But what about uneven distributions, where some proteins are more densely and non-randomly packed (significant and functional) at some sites of the membrane than at others, e.g.

By which mechanisms (forces, signals or structures) are these proteins led to their targets?

Maybe it depends, and there are different mechanisms. These I came up with (by contemplating first principles):

  • uneven distribution of generation sites inside the cell (due to what?)

  • uneven distribution of origins of attracting signals inside the membrane (due to what?)

  • some "self-attracting" forces or signals (leading to accumulation by positive feedback)

  • microtubules

Which mechanism is — possibly — predominant?


Related questions:

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This is a great question. A comprehensive answer would be beyond the scope of an answer on a forum like this. I will summarize the best I can here, but if you are really interested in this you should look at some of the work by Randy Schekman and Tom Rapoport, who have done a lot of pioneering work in this field and have papers from more than two decades ago on their lab websites. I'll talk about membrane proteins generally, but I'm not sure what the state of the field is for Na+ channels specifically, so I can't comment too much on that particular case. Many of the details of the processes I will mention are still areas of active research, so I will try to stick mainly to what has been well-characterized (to the best of my knowledge).

To restate the problem, proteins are generally synthesized in the lumen of the endoplasmic reticulum, which is an aqueous environment similar to the cytosol in many (but not all) ways. However, membrane proteins, which are not stable in aqueous environments, must:

1) Find a way from the ER lumen into a membrane.
2) Get from the ER into the correct membrane so they may perform their cellular function.

We will start with step 1, but the key to both is a critical but often underappreciated aspect of protein biology called the signal peptide. The signal peptide is simply an N-terminal sequence of amino acids that precedes what we would normally think of as the beginning of a mature protein. It is relatively short, usually only ~30 amino acids in length. It is cleaved off the mature protein by a protease once the protein is folded and in the membrane. Until that time, the signal peptide serves as a molecular marker that indicates where the nascent protein should be heading and how it should be handled. Not surprisingly, there are many different signal peptides that serve multiple functions, and they are not only used for membrane proteins.

So let's say we are in the ER lumen, and have some mRNA coding for a membrane protein that is destined for the plasma membrane. The first amino acids that will emerge from the ribosome is the signal sequence, in this case a specific signal sequence indicating that this is to be a plasma membrane protein. Once the signal sequence emerges from the ribosome, it is recognized by a ribonucleoprotein complex (that is, a complex of RNA and protein) called the signal recognition particle. Once the SRP binds to the signal peptide, translation is halted, and the whole complex moves to the ER membrane, where it forms a complex with another large protein complex called the translocon. I can't go into the intricacies of these complexes and their functions in this answer alone, but the simple description is that the translocon contains an ATPase that can insert the membrane protein into the ER membrane as it is translated, with the correct orientation. The hydrolysis of ATP provides energy to move the emerging polypeptide chain into the hydrophobic membrane, where chaperones help it fold. This process is in part driven by the recognition of hydrophobic transmembrane regions of the proteins by the translocon. It can also move soluble, cytosolic proteins across the membrane through a similar mechanism.

Now that the protein has been translocated, a peptidase will cleave the signal sequence off the protein. From here, sorting signals will take over. Generally, these are simple sequence motifs in the first transmembrane domain that act similarly to a signal sequence, but they are not cleaved. However, sorting signals can be stretches of peptide throughout the protein too, in some cases.

These sequence motifs will be recognized by cell trafficking machinery. Without going into too much detail, the proteins will be gathered into vesicles, and transported to other organelles. Usually, the first stop for proteins is the golgi apparatus, which is typically where many post-translational modifications, such as glycosylation, take place. I am a biochemist and not a cell biologist, so I am not the most qualified to go into the details of subcellular trafficking. Suffice it to say, once the protein is finished being processed in the golgi, it will be trafficked into other organelles, such as the plasma membrane using vesicle transport as before. From my understanding, the protein will be sorted into the proper vesicles based on its sorting signals, as well as other markers (in some cases, certain post-translational modifications on certain proteins can influence its trafficking). The vesicles recognize the proper destination membrane in part by the lipid composition of that membrane. For example, phosphoinositides have extensive influence on membrane trafficking, and many membranes can be differentiated by their phosphoinositide signature.

Anyway, that is a very broad overview of the answer to your question. I'm sorry I can't comment too much on the intricacies of cellular trafficking, I don't quite have the expertise to go through that literature quickly enough to answer your question in a reasonable time frame. I hope this is helpful in pointing you in the right direction, and good luck!

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Is active transport an answer? With special signalling and interaction peptides inside of the protein, proteins can be targeted to different sublocations.If you are interested in how Na+ channels accumulate at the AIS, read for example Gasser et al. 2012, that is a very nice paper that shows the ankyrin binding motif is sufficient to cluster Na+ channels at the AIS.

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  • $\begingroup$ Might be. But HOW are the proteins targeted to different sublocations (specifically)? I'm probably NOT interested in how Na+ ions do accumulate anywhere. $\endgroup$ – Hans-Peter Stricker Nov 24 '17 at 20:25
  • $\begingroup$ But I may be misled. Maybe Na+ accumulation is the answer. $\endgroup$ – Hans-Peter Stricker Nov 24 '17 at 20:26
  • $\begingroup$ Sorry, I meant channels, was missing the word. $\endgroup$ – anki Nov 24 '17 at 20:31

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