Examples of passive membrane transport proteins that only transport in one direction and their mechanism

Question

I would like to know about those transporters with alternating-access-type mechanism, that can only efficiently shuttle molecules in one direction but the other direction is severely kinetically inhibited. From this question I know that they exist, but Google searches are futile in finding examples. Wikipedia is not much help, either. I also skimmed the seventh chapter of the Campbell biology book, about the structure and function of the cell membrane, but there was no clue.

More generally, I have found examples of enzymes that is inhibited only in one direction, such as F1-ATPase (even without the inhibitory epsilon subunit) with its mechanism of ADP inhibition, which primarily affect ATP hydrolysis and not ATP synthesis. I just have not found examples of this in passive transporters specifically.

Furthermore, is the mechanism of unidirectional inhibition inherent to the transporter domain itself, or does it require a separate domain, as in the case of the voltage-gated ion channels, to sense the gradient flowing in the other direction and then inhibit the transporter domain?

Is there even an universal mechanism?

My guess for an universal mechanism would be the former, as I am aware of the basic kinetics of the active ABC transporters, in that they preferentially open to one side of the membrane.

Answer 1

Voltage-gated proton channels are passive transmembrane transport proteins that will only transport protons in one direction. These channels will be open when there is a lower pH in the cytoplasm, allowing protons to flow out of the cell, but will close when the pH is higher in the cytoplasm, not allowing protons into the cell. [1] In this case, the protein does not sense the direction of flow, but rather opens only in conditions where one direction of flow is possible.

Most voltage-gated proton channels have a separate voltage-sensing domain from their pore domain. However, H_V1 does not have separate voltage-sensing and pore domains. [2] Therefore, neither combined nor separate regulatory and transport domains is universal. I am not aware of the mechanism in either case, or whether their are other proteins with different mechanisms.

1. DeCoursey, T. E. (2003). Voltage-gated proton channels and other proton transfer pathways. Physical Rev, 83, 475-579. https://doi.org/10.1152/physrev.00028.2002
2. DeCoursey, T. E., Morgan, D., Musset, B., & Cherney, V. V. (2016). Insights into the structure and function of H_V1 from a meta-analysis of mutation studies. J Gen Physiol, 148(2), 97-118. https://doi.org/10.1085%2Fjgp.201611619

Answer 2

I'm fascinated by such questions @symmetrickittens so i'll just post a first pass here.

There are probably too many families which are not characterized right now to make a comprehensive answer. This review estimates that 21% of prokaryote proteins are integral membrane proteins. A large percentage of these are of unknown function, and there are many variants of each gene which may be functionally distinct. This last reference just talks about the human proteome. Each new genome sequenced has a substantial proportion 20-40% of protein products predicted with no clear function [anecdotal recollection from reading genome papers].

As such there are some nice reviews taking some fat slices of sequences which are really exciting to read (if you are a nerd like me). The above reference predicts 1700 structural membrane protein families. This review of human membrane proteins discusses 89 transporter families but leaves 41% of membrane proteins uncharacterized. Remembering that we diverged from eubacteria the better part of a billion years ago, there are probably well more than 89 protein transporter families!

A good fraction (majority?) of research is focused on human biology. If you can get used to the idea, then starting with the human transport protein proteome is not a bad place to start. Here is a link to the Transporter Classification Database from the Saier Lab at UCSD. They have proposed 1708 families of transporters. I sincerely doubt they are promising not to discover more!