Structure of a receptor-binding fragment of reelin and mutational analysis reveal a recognition mechanism similar to endocytic receptors

Norihisa Yasui, Terukazu Nogi, Tomoe Kitao, Yoshimi Nakano, Mitsuharu Hattori, Junichi Takagi

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Reelin, a large secreted protein implicated in the cortical develop ment 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-Å 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 lipoprotein receptors.

Original languageEnglish
Pages (from-to)9988-9993
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number24
DOIs
Publication statusPublished - Jun 12 2007
Externally publishedYes

Keywords

  • Brain development
  • X-ray crystallography

ASJC Scopus subject areas

  • General

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