The low density lipoprotein receptor (LDLR) binds and internalizes low density lipoprotein (LDL). At the mildly acidic pH of the sorting endosomes, LDL is released from the receptor and the receptor recycles back to the cell membrane. Mutations in the LDLR gene may disrupt the normal function of the LDLR in different ways. Class 5 mutations result in receptors that are able to bind and internalize LDL, but they fail to release LDL in the sorting endosomes and fail to recycle. Instead they are rerouted to the lysosomes for degradation. However, the underlying mechanism remains to be determined. To study the role of the cytoplasmic domain of the LDLR for rerouting Class 5 mutants to the lysosomes, we have performed studies to determine whether Class 5 mutants caused by mutations E387K or V408M are degraded when the cytoplasmic domain has been altered or deleted. As determined by confocal laser-scanning microscopy, these mutant LDLR were inserted into the cell membrane and were able to internalize LDL. As determined by Western blot analysis, Class 5 mutants without a cytoplasmic domain still were degraded after binding LDL. Thus, the cytoplasmic domain does not play a role in rerouting Class 5 mutant LDLR to the lysosomes. Rather, one may speculate that sterical hindrance may prevent Class 5 mutants with bound LDL from entering the narrow recycling tubules of the sorting endosome. (C) 2011 Elsevier Inc. All rights reserved.