Sorting motifs in the intracellular domain of the low density lipoprotein receptor interact with a novel domain of sorting nexin-17.
The low density lipoprotein (LDL) receptor plays a major role in maintaining human plasma cholesterol levels and mutations in the gene cause familial hypercholesterolemia. The LDL receptor (LDLR) pathway has been well characterized, but little is known of proteins involved in its complex intracellular sorting and trafficking. Sorting nexin 17 (SNX17) has recently been implicated in LDLR intracellular trafficking. We show here that endogenous SNX17 is highly expressed in several cell types and is localized partially in early endosomes. We found that the PX domain of SNX17 is required for its endosomal localization but does not interact directly with the LDL receptor. A novel domain containing a FERM-like domain of SNX17 is needed for its interaction with the LDL receptor. Mutations in the NPXY motif of the LDL-receptor cytoplasmic tail that disrupt internalization also disrupt its interaction with SNX17, whereas mutations elsewhere had little effect. When transiently overexpressed in Chinese hamster ovary cells, SNX17 localized to large vesicular structures and disrupted normal trafficking of the LDL receptor in a PX domain-dependent manner. These results suggest that SNX17 plays a role in the cellular trafficking of the LDL receptor through interaction with the NPVY motif in its cytoplasmic domain and interaction of the PX domain with subcellular membrane compartments.
Burden
Jemima J
JJ
Lipoprotein Group, Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, London W12 ONN, United Kingdom.
Sun
Xi-Ming
XM
García
Ana Bárbara García
AB
Soutar
Anne K
AK
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D008969:Molecular Sequence Data; D010449:Peptide Mapping; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D011973:Receptors, LDL; C487895:SNX17 protein, human; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins