Structural studies of reelin N-terminal region provides insights into a unique structural arrangement and functional multimerization

Masamichi Nagae, Kei Suzuki, Norihisa Yasui, Terukazu Nogi, Takao Kohno, Mitsuharu Hattori, Junichi Takagi

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

The large, secreted glycoprotein reelin regulates embryonic brain development as well as adult brain functions. Although reelin binds to its receptors via its central part, the N-terminal region directs multimer formation and is critical for efficient signal transduction. In fact, the inhibitory antibody CR-50 interacts with the N-terminal region and prevents higher-order multimerization and signalling. Reelin is a multidomain protein in which the central part is composed of eight characteristic repeats, named reelin repeats, each of which is further divided by insertion of a epidermal growth factor (EGF) module into two subrepeats. In contrast, the N-terminal region shows unique 'irregular' domain architecture since it comprises three consecutive subrepeats without the intervening EGF module. Here, we determined the crystal structure of the murine reelin fragment named RX-R1 including the irregular region and the first reelin repeat at 2.0-Å resolution. The overall structure of RX-R1 has a branched Y-shaped form. Interestingly, two incomplete subrepeats cooperatively form one entire subrepeat structure, though an additional subrepeat is inserted between them. We further reveal that Arg335 of RX-R1 is crucial for binding CR-50. A possible self-association mechanism via the N-terminal region is proposed based on our results.

Original languageEnglish
Pages (from-to)555-564
Number of pages10
JournalJournal of biochemistry
Volume169
Issue number5
DOIs
Publication statusPublished - May 1 2021
Externally publishedYes

Keywords

  • epitope mapping
  • inhibitory antibody CR-50
  • irregular region
  • protein crystallography
  • reelin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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