School of Medicine
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Israel Juarez Contreras
Postdoctoral Scholar, Biochemistry
Current Research and Scholarly InterestsSterols are the most abundant lipid in the plasma membrane. Their structure is deeply conserved, built though a long iterative evolutionary process whose end products are the topology of the fused steroid ring system and the structure of the aliphatic tail extending from it. Together these let the molecule pack tightly against the acyl chains of neighboring lipids, which is how sterols reinforce the membrane and set its fluidity. This same interaction produces a second effect. Sterols associate preferentially with saturated lipids, particularly sphingolipids, and that preference sorts the bilayer into ordered domains, often called lipid rafts, which concentrate certain proteins and exclude others.
The Bloch hypothesis holds that the sterol biosynthetic pathway was progressively selected for membrane function, with each step yielding a molecule better suited to the bilayer than the one before it. Fluidity has historically been taken as the property under selection, but it is not the only one. Rebuilding ergosterol biosynthesis stepwise in living yeast showed that domain formation imposes its own demands, and that the two properties are not optimized by the same modifications. The pathway alternates between them, arriving at structures that regulate fluidity and organization together rather than either alone. A further design principle follows from this. The pairing between a sterol and the acyl chain length of its partner sphingolipid is highly specific. Replacing the native pathway in yeast with cholesterol biosynthesis abolished the domains ergosterol supports, since ergosterol pairs with the very long acyl chains of fungal sphingolipids while cholesterol pairs with the shorter chains of mammalian membranes.
These principles, observed in fungi, carry direct consequences for mammals, where cholesterol occupies two distinct pools. One is structural, held in complex with sphingolipids and other lipids. The other is a residual fraction, free or accessible that carries out essential roles in signaling and homeostasis. Accessible cholesterol is defined operationally, by what a probe can bind, but what it corresponds to physiochemically remains open. My central goal is to define accessible cholesterol through a more rigorous biophysical lens and connect that definition to the machinery in cells.
