Abstract
The LDL receptor (LDLR) relies upon endocytic adaptor proteins for internalization of lipoproteins. The results of this study show that the LDLR adaptor autosomal recessive hypercholesterolemia protein (ARH) requires nitric oxide to support LDL uptake. Nitric oxide nitrosylates ARH at C199 and C286, and these posttranslational modifications are necessary for association of ARH with the adaptor protein 2 (AP-2) component of clathrin-coated pits. In the absence of nitrosylation, ARH is unable to target LDL-LDLR complexes to coated pits, resulting in poor LDL uptake. The role of nitric oxide on LDLR function is specific for ARH because inhibition of nitric oxide synthase activity impairs ARH-supported LDL uptake but has no effect on other LDLR-dependent lipoprotein uptake processes, including VLDL remnant uptake and dab2-supported LDL uptake. These findings suggest that cells that depend upon ARH for LDL uptake can control which lipoproteins are internalized by their LDLRs through changes in nitric oxide.
Highlights
The LDL receptor (LDLR) relies upon endocytic adaptor proteins for internalization of lipoproteins
The reason to suspect that autosomal recessive hypercholesterolemia protein (ARH) might be subject to posttranslational modification originated from the first immunoblots of ARH, which showed that ARH exists in two forms of differing electrophoretic mobility [17]
To ensure that the difference in mobility did not result from proteolysis, we introduced into HEK293 cells C-terminally V5-tagged human ARH variants encoding full-length ARH, an N-terminal fragment of ARH, or a C-terminal fragment of ARH
Summary
The LDL receptor (LDLR) relies upon endocytic adaptor proteins for internalization of lipoproteins. Uptake of VLDL remnants does not require ARH, dab, or a functional FDNPVY sequence because binding of VLDL remnants to the LDLR induces a separate endocytic process that involves a second internalization motif on the LDLR cytoplasmic domain [10]. It is not clear why the LDLR needs an induced process for VLDL remnant uptake when the FDNPVY-dependent process can internalize both LDL and VLDL remnants, nor why the FDNPVY process utilizes both the ARH and dab adaptors when either adaptor is sufficient to support lipoprotein uptake by the LDLR. Why hepatocytes and leukocytes normally rely upon ARH is unclear because both cell types lose their dependence on ARH for LDL uptake when dab expression is induced
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
