The protein autosomal recessive hypercholesterolemia (ARH) supports LDLR-dependent LDL uptake, but is dispensable for LDLR-dependent VLDL uptake.
Our work has examined the molecular mechanisms responsible for this lipoprotein specificity. We have shown that the LDLR has two internalization sequences:
- The FDNPVY sequence is a constitutive uptake sequence that supports internalization irrespective of whether or not lipoprotein is bound.
- The HIC sequence is a VLDL-induced uptake sequence that only supports internalization when VLDL is bound. ARH binds to the FDNPVY sequence and supports the constitutive uptake pathway, which is necessary for LDL uptake.
In recent work we showed that ARH activity requires nitrosylation, a post-translational modification of cysteine sulfhydryls by nitric oxide. Nitrosylation activates the ability of ARH to bind to components of clathrin coated pits and is necessary for ARH to drive LDLRs to this endocytic structure.
One consequence of ARH involvement is that the distribution of receptors between the cell surface and intracellular compartments shifts toward the latter. Loss of ARH function increases the number of surface receptors at steady state and this increase can improve VLDL uptake.
Thus, regulation of nitric oxide levels allows cells that use ARH to control whether the LDLR internalizes both LDL and VLDL or functions as a super-potent VLDL receptor.
- Zhao Z, Pompey S, Dong H, Weng J, Garuti R, Michaely P. S-nitrosylation of ARH is required for LDL uptake by the LDL receptor. J Lipid Res. 2013 54:1550-9. PMID: 23564733.
- Michaely P, Zhao Z, Li WP, Garuti R, Huang L, Hobbs HH, Cohen JC. Identification of a VLDL-induced, FDNPVY-independent internalization mechanism for the LDLR. EMBO J 2007 26: 3273-82. PMID: 17581630.
- Jones C, Garuti R, Michaely P, Li WP, Maeda N, Cohen JC, Herz J, Hobbs HH. Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia. J Clin Invest. 2007 117: 165-174. PMID: 17200716.