Which adapter protein interacts with the NPXY motif of LDL receptors?
LDL receptor internalization requires highly specific recognition cytosolic tail by endocytic co-adaptors bridging to clathrin lattice enhancing efficiency. Tail 50 amino acids contains conserved FXNPXY motif positions 802-807 forming tight beta-turn favored aromatic phenylalanine tyrosine. PTB domains autosomal recessive hypercholesterolemia protein ARH LDLRAP1 and Dab2 Disabled-2 liver recognize NPXY tyrosine hydrophobic pocket interacting also basic residues upstream motif. Adaptors contain additional trafficking domains: clathrin box binding heavy chain terminal domain, AP2 beta2 appendage binding DxF sites, N-terminal PIP2-binding FERM-like domain anchoring plasma membrane. Thus co-adaptor physically links receptor tail simultaneously phosphoinositide clathrin AP2 ensuring rapid clustering coated pits half-life two minutes. Direct interaction NPXY to AP2 mu2 very weak; co-adaptor amplifies specificity. AP1 TGN via gamma adaptin, AP3 lysosome-related organelles membranes. Mutation Tyr807Cys causing FH class 4 prevents ARH binding receptors remain diffusely surface normal LDL binding but severely reduced uptake leading hypercholesterolemia reflecting sorting defect not binding defect, highlighting co-adaptor necessity and pathway logic.
Ref: He et al., Biochemistry: NPXY motif of LDLR binds ARH and AP2 adaptor.