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 language | English |
|---|---|
| Pages (from-to) | 9988-9993 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 104 |
| Issue number | 24 |
| DOIs | |
| Publication status | Published - Jun 12 2007 |
| Externally published | Yes |
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Keywords
- Brain development
- X-ray crystallography
ASJC Scopus subject areas
- Genetics
- General
Cite this
Structure of a receptor-binding fragment of reelin and mutational analysis reveal a recognition mechanism similar to endocytic receptors. / Yasui, Norihisa; Nogi, Terukazu; Kitao, Tomoe; Nakano, Yoshimi; Hattori, Mitsuharu; Takagi, Junichi.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 24, 12.06.2007, p. 9988-9993.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Structure of a receptor-binding fragment of reelin and mutational analysis reveal a recognition mechanism similar to endocytic receptors
AU - Yasui, Norihisa
AU - Nogi, Terukazu
AU - Kitao, Tomoe
AU - Nakano, Yoshimi
AU - Hattori, Mitsuharu
AU - Takagi, Junichi
PY - 2007/6/12
Y1 - 2007/6/12
N2 - 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.
AB - 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.
KW - Brain development
KW - X-ray crystallography
UR - http://www.scopus.com/inward/record.url?scp=34547173322&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547173322&partnerID=8YFLogxK
U2 - 10.1073/pnas.0700438104
DO - 10.1073/pnas.0700438104
M3 - Article
VL - 104
SP - 9988
EP - 9993
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 24
ER -