Structural basis for specific recognition of reelin by its receptors.
Apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor, members of the low-density lipoprotein receptor (LDLR) protein family, function as neuronal receptors for a secreted glycoprotein reelin during brain development. In both receptors, the first LDLR class A (LA1) module is sufficient to bind reelin. Analysis of a 2.6 A crystal structure of the reelin receptor-binding fragment in complex with the LA1 of ApoER2 revealed that Lys2467 of reelin is recognized by both a conserved Trp residue and calcium-coordinating acidic residues from LA1, which together with Lys2360 plays a critical role in the interaction. This "double-Lys" recognition mode is, in fact, shared among other LDLR family proteins in ligand binding. The interface between reelin and LA1 covers a small surface area of approximately 350 A(2) on each side, which ensures a stable complex formation under physiological conditions. An examination of structure-guided mutagenesis on interface residues revealed key features of this interaction.
Yasui
Norihisa
N
Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Suita, Osaka, Japan.
Nogi
Terukazu
T
Takagi
Junichi
J
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry* / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D016326:Extracellular Matrix Proteins / Q000737:chemistry* / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D018110:Receptors, Lipoprotein; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases