Title : Structure of a
receptor-binding
fragment of
reelin and mutational analysis reveal a recognition mechanism similar to endocytic
receptors
Abstract :
- Reelin , a large secreted protein implicated in the cortical development of the mammalian brain, is composed of eight tandem concatenations of "reelin repeats" and binds to neuronal receptors belonging to the low-density lipoprotein receptor gene family
- We found that both receptor-binding and subsequent Dab1 phosphorylation occur solely in the segment spanning the fifth and sixth reelin repeats (R5-6)
- Monomeric fragment exhibited a suboptimal level of signaling activity and artificial oligomerization resulted in a 10-fold increase in activity, indicating the critical importance of higher-order multimerization in physiological reelin
- A 2.0-A crystal structure from the R5-6 fragment revealed not only a unique domain arrangement wherein two repeats were aligned side by side with the same orientation, but also the unexpected presence of bound Zn ions
- Structure-guided alanine mutagenesis of R5-6 revealed that two Lys residues ( Lys-2360 and Lys-2467 ) constitute a central binding site for the low-density lipoprotein receptor class A module in the receptor , indicating a strong similarity to the ligand recognition mode shared among the endocytic lipo protein receptors