NTR: sterol:proton antiporter activity

[hattrill]

Please provide as much information as you can:

• Suggested term label:

• sterol:proton antiporter activity

• Definition (free text)
  Enables the transfer of a sterol from one side of a membrane to the other according to the reaction: H+(out) + sterol(in) = H+(in) + sterol(out).

• Reference, in format PMID:#######
  PMID:10735876

• Gene product name and ID to be annotated to this term
  Npc1a, FBgn0024320

• Parent term(s)
  GO:0170055 lipid transmembrane transporter activity
  GO:1901618 organic hydroxy compound transmembrane transporter activity
  GO:0015297 antiporter activity

• Cross-references

• TCBD:2.A.6

• Any other information
  Add as possible replacement term for GO:0015248 obsolete sterol transporter activity

[deustp01]

• Enables the transfer of a sterol from one side of a membrane to the other according to the reaction: ATP + H2O + sterol(in) = ADP + phosphate + sterol(out)

Should this reaction also have a proton as an output, in line with, e.g., RHEA:39103 "ATP + H2O + sitosterol(in) = ADP + H(+) + phosphate + sitosterol(out)"?

[hattrill]

Sorry, pasted in wrong definition! (that was for another ticket)

Enables the transfer of a sterol from one side of a membrane to the other according to the reaction: H+(out) + sterol(in) = H+(in) + sterol(out).

I'll corrrect the above

[hattrill]

As sterol is a class of molecule, don't think there's a Rhea reaction for this.

[deustp01]

Rhea does allow reactions for molecule classes, including "sterol". It happens not to have a reaction yet for this particular transport process, but it looks like the needed reaction would be in scope.

[raymond91125]

Is PMID:10735876 the correct reference, @hattrill, perhaps PMID:31543266 "Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins"?
And https://www.tcdb.org/search/result.php?tc=2.A.6.6.1 seems to be the more precise XREF.

[raymond91125]

+[Term]
+id: GO:0160188
+name: sterol:proton antiporter activity
+namespace: molecular_function
+def: "Enables the transfer of a sterol from one side of a membrane to the other according to the reaction: H+(out) + sterol(in) = H+(in) + sterol(out)." [PMID:31543266]
+xref: TC:2.A.6.6.1
+is_a: GO:0015297 ! antiporter activity
+intersection_of: GO:0015297 ! antiporter activity
+intersection_of: has_primary_input CHEBI:15378 ! hydron
+intersection_of: has_primary_input CHEBI:15889 ! sterol
+property_value: term_tracker_item "#27883" xsd:anyURI
+created_by: rynl
+creation_date: 2024-05-15T00:33:06Z

[raymond91125]

Let me know if anything needs fixing. Thanks.

[hattrill]

Hi @raymond91125 sorry to be a pain.
I reviewed this and I am wrong about the mechanism for sterol transport. The bacterial RNDs are H+ antiporters (but not for sterols), but the eukaryotic sterol "transporters" are pH-dependent but defitely not antiporters and I think are better described by the sterol transfer activity term - although I need to check this further.
The upshot is, could you obsolete this term as I requested it in error. Thanks!

[raymond91125]

@hattrill PMID:31543266 Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins states:
"NCR1 has its N-terminal domain (NTD) positioned to deliver a sterol to a tunnel connecting NTD to the luminal membrane leaflet 50 Å away. A sterol is caught inside this tunnel during transport, and a proton-relay network of charged residues in the transmembrane region is linked to this tunnel supporting a proton-driven transport mechanism. "
Thus it seems that this activity is valid.
Also TCDB classifies NPC1 under 2.A.6 RND super family, which "all probably catalyze substrate efflux via an H+ antiport mechanism".

[hattrill]

@raymond91125 yes, that is what I based the initial request on, but it seems that the proton-dependency varies for RND families. For eukaryotic NPC1-type transporters, they are tranporting sterols from inside the acidic lumen of a lysosome/late endolysome/vacuole, so the proton grandient is inside-to-out and that the proton accompanies the sterol. In PMID:29577985 (RND transporters in the living world) they say that "since the endosome lumen is more acidic than the cytosol, NPC1 appears to function, unusually among RND transporters, as a proton/ligand symporter, rather than an antiporter".

Looking at this 2024 paper on the yeast protein, [PMID:38568972 (Conformational changes in the Niemann-Pick type C1 protein NCR1 drive sterol translocation)] (https://pubmed.ncbi.nlm.nih.gov/38568972/), it suggests that a proton is released to the cytosol and so would be symport (although the mechanism is very complex, but I think that is the correct interpretation). As they suggest that the transporter releases the sterol into the membrane, I am not 100% sure if this comes under TM transporter - I am erring on that side, rather than an 'insertase' or 'carrier' because of the channel and the crossing of a membrane and I think this is the general view of them.

For the bacterial RNDs, they are definitely proton antiporters PMID:38689873, but I cannot find an example of them transporting sterols - seem to be mainly involved in drug efflux.

So, perhaps "sterol:proton symporter activity" is what I want, but I am a bit reluctant to commit to that.

[raymond91125]

Thanks for the clarification.