Table 1.

Arguments for and against different models by which PTCH regulates SMO.

Model1: PTCH reduces accessibility of (ciliary) cholesterol for SMO

Pro: Unless a different sterol or steroidal detergent is added during purifications, the sterol-like densities seen in PTCH1 and SMO structures are likely cholesterol.

Con:

- Alteration of cholesterol distribution by PTCH would have pleiotropic effects.

- SMO activity would be affected by various other cholesterol transporters.

- An ultimate acceptor for cholesterol removed away from SMO is required.

Model 2: PTCH removes an oxysterol agonist from SMO

Pro: specific

Con:

- affinity << abundance (except 24(S),25-hydroxycholesterol, see text)

- no genetic evidence (does not apply for 24(S),25-hydroxycholesterol, see text)

Model 3: SMO requires cholesterol but PTCH inhibits SMO via a sterol antagonist

Pro:

- specific

- evidence for a positive effect of MCD under certain conditions

- can explain non-cell-autonomous inhibition of SMO by PTCH

Con: hard to genetically disentangle a negative effect of 7-dehydrocholesterol derivatives from the positive effect of cholesterol

Vikas Daggubati: Writing- Original draft preparation, Writing- Reviewing and Editing. David R. Raleigh: Writing- Reviewing and Editing. Navdar Sever: Conceptualization, Writing- Original draft preparation, Writing- Reviewing and Editing, Supervision.