Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers.
Proteins of the low-density lipoprotein receptor family transport cholesterol-carrying particles into cells, clear protease-inhibitor complexes from the circulation, participate in biological signaling cascades, and even serve as viral receptors. These receptors utilize clusters of cysteine-rich LDL receptor type-A (LA) modules to bind many of their ligands. Recent structures show that these modules typically exhibit a characteristic binding mode to recognize their partners, relying primarily on electrostatic complementarity and avidity effects. The dominant contribution of electrostatic interactions with small interface areas in these complexes allows binding to be regulated by changes in pH via at least two distinct mechanisms. The structure of the subtilisin/kexin family protease PCSK9, a newly identified molecular partner of the LDLR also implicated in LDL-cholesterol homeostasis, also raises the possibility that the LDLR and its related family members may employ other strategies for pH-sensitive binding that have yet to be uncovered.
Blacklow
Stephen C
SC
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. sblacklow@rics.bwh.harvard.edu
D000818:Animals; D001053:Apolipoproteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006639:Histidine / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D026563:LDL-Receptor Related Protein-Associated Protein / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011487:Protein Conformation; D011973:Receptors, LDL / Q000737:chemistry* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism
D001053:Apolipoproteins; D026563:LDL-Receptor Related Protein-Associated Protein; D008024:Ligands; D011973:Receptors, LDL; D006639:Histidine; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases