Origins of peptide selectivity and phosphoinositide binding revealed by structures of Disabled-1 PTB domain complexes

Peggy C. Stolt; Hyesung Jeon; Hyun Kyu Song; Joachim Herz; Michael J. Eck; Stephen C. Blacklow

doi:10.1016/S0969-2126(03)00068-6

Origins of peptide selectivity and phosphoinositide binding revealed by structures of Disabled-1 PTB domain complexes

Peggy C. Stolt, Hyesung Jeon, Hyun Kyu Song, Joachim Herz, Michael J. Eck, Stephen C. Blacklow

Research output: Contribution to journal › Article › peer-review

100 Citations (Scopus)

Abstract

Formation of the mammalian six-layered neocortex depends on a signaling pathway that involves Reelin, the very low-density lipoprotein receptor, the apolipoprotein E receptor-2 (ApoER2), and the adaptor protein Disabled-1 (Dab1). The 1.5 Å crystal structure of a complex between the Dab1 phosphotyrosine binding (PTB) domain and a 14-residue peptide from the ApoER2 tail explains the unusual preference of Dab1 for unphosphorylated tyrosine within the NPxY motif of the peptide. Crystals of the complex soaked with the phosphoinositide PI-4,5P₂ (PI) show that PI binds to conserved basic residues on the PTB domain opposite the peptide binding groove. This finding explains how the Dab1 PTB domain can simultaneously bind PI and the ApoER2 tail. Recruitment of the Dab1 PTB domain to PI-rich regions of the plasma membrane may facilitate association with the Reelin receptor cytoplasmic tails to transduce a critical positional cue to migrating neurons.

Original language	English
Pages (from-to)	569-579
Number of pages	11
Journal	Structure
Volume	11
Issue number	5
DOIs	https://doi.org/10.1016/S0969-2126(03)00068-6
Publication status	Published - 2003 May 1
Externally published	Yes

Bibliographical note

Funding Information:
This research is supported by National Institutes of Health grants to S.C.B. (HL61001) and M.J.E. S.C.B. is a Pew Scholar in the Biomedical Sciences and an Established Investigator of the American Heart Association. M.J.E. is a Scholar of the Leukemia and Lymphoma Society of America. P.C.S. is an NSF predoctoral fellow, and H.J. is an AHA postdoctoral fellow. We thank Anand Saxena and the staff of the X12C beamline at BNL and the Research Resource for Macromolecular Crystallography at the National Synchrotron Light Source funded by the NIH National Center for Research Resources and the DOE Office of Biological and Environmental Research. This work is also based upon research conducted at the Cornell High Energy Synchrotron Source (CHESS), which is supported by the National Science Foundation under award DMR-9311772, with macromolecular diffraction at the CHESS (MacCHESS) facility, which is supported by award RR-01646 from the NIH. J.H. is supported by grants from the NIH (HL20948, HL63762, and NS43408), the Alzheimer Association, and the Perot Family Foundation and is the recipient of a Wolfgang-Paul Award by the Humboldt Foundation.

Keywords

ApoER2
Disabled
Lipoprotein receptor
Phosphoinositide
Reelin signaling
X-ray crystallography

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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10.1016/S0969-2126(03)00068-6

Cite this

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title = "Origins of peptide selectivity and phosphoinositide binding revealed by structures of Disabled-1 PTB domain complexes",

abstract = "Formation of the mammalian six-layered neocortex depends on a signaling pathway that involves Reelin, the very low-density lipoprotein receptor, the apolipoprotein E receptor-2 (ApoER2), and the adaptor protein Disabled-1 (Dab1). The 1.5 {\AA} crystal structure of a complex between the Dab1 phosphotyrosine binding (PTB) domain and a 14-residue peptide from the ApoER2 tail explains the unusual preference of Dab1 for unphosphorylated tyrosine within the NPxY motif of the peptide. Crystals of the complex soaked with the phosphoinositide PI-4,5P2 (PI) show that PI binds to conserved basic residues on the PTB domain opposite the peptide binding groove. This finding explains how the Dab1 PTB domain can simultaneously bind PI and the ApoER2 tail. Recruitment of the Dab1 PTB domain to PI-rich regions of the plasma membrane may facilitate association with the Reelin receptor cytoplasmic tails to transduce a critical positional cue to migrating neurons.",

keywords = "ApoER2, Disabled, Lipoprotein receptor, Phosphoinositide, Reelin signaling, X-ray crystallography",

author = "Stolt, {Peggy C.} and Hyesung Jeon and Song, {Hyun Kyu} and Joachim Herz and Eck, {Michael J.} and Blacklow, {Stephen C.}",

note = "Funding Information: This research is supported by National Institutes of Health grants to S.C.B. (HL61001) and M.J.E. S.C.B. is a Pew Scholar in the Biomedical Sciences and an Established Investigator of the American Heart Association. M.J.E. is a Scholar of the Leukemia and Lymphoma Society of America. P.C.S. is an NSF predoctoral fellow, and H.J. is an AHA postdoctoral fellow. We thank Anand Saxena and the staff of the X12C beamline at BNL and the Research Resource for Macromolecular Crystallography at the National Synchrotron Light Source funded by the NIH National Center for Research Resources and the DOE Office of Biological and Environmental Research. This work is also based upon research conducted at the Cornell High Energy Synchrotron Source (CHESS), which is supported by the National Science Foundation under award DMR-9311772, with macromolecular diffraction at the CHESS (MacCHESS) facility, which is supported by award RR-01646 from the NIH. J.H. is supported by grants from the NIH (HL20948, HL63762, and NS43408), the Alzheimer Association, and the Perot Family Foundation and is the recipient of a Wolfgang-Paul Award by the Humboldt Foundation.",

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AU - Jeon, Hyesung

AU - Song, Hyun Kyu

AU - Herz, Joachim

AU - Eck, Michael J.

AU - Blacklow, Stephen C.

N1 - Funding Information: This research is supported by National Institutes of Health grants to S.C.B. (HL61001) and M.J.E. S.C.B. is a Pew Scholar in the Biomedical Sciences and an Established Investigator of the American Heart Association. M.J.E. is a Scholar of the Leukemia and Lymphoma Society of America. P.C.S. is an NSF predoctoral fellow, and H.J. is an AHA postdoctoral fellow. We thank Anand Saxena and the staff of the X12C beamline at BNL and the Research Resource for Macromolecular Crystallography at the National Synchrotron Light Source funded by the NIH National Center for Research Resources and the DOE Office of Biological and Environmental Research. This work is also based upon research conducted at the Cornell High Energy Synchrotron Source (CHESS), which is supported by the National Science Foundation under award DMR-9311772, with macromolecular diffraction at the CHESS (MacCHESS) facility, which is supported by award RR-01646 from the NIH. J.H. is supported by grants from the NIH (HL20948, HL63762, and NS43408), the Alzheimer Association, and the Perot Family Foundation and is the recipient of a Wolfgang-Paul Award by the Humboldt Foundation.

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N2 - Formation of the mammalian six-layered neocortex depends on a signaling pathway that involves Reelin, the very low-density lipoprotein receptor, the apolipoprotein E receptor-2 (ApoER2), and the adaptor protein Disabled-1 (Dab1). The 1.5 Å crystal structure of a complex between the Dab1 phosphotyrosine binding (PTB) domain and a 14-residue peptide from the ApoER2 tail explains the unusual preference of Dab1 for unphosphorylated tyrosine within the NPxY motif of the peptide. Crystals of the complex soaked with the phosphoinositide PI-4,5P2 (PI) show that PI binds to conserved basic residues on the PTB domain opposite the peptide binding groove. This finding explains how the Dab1 PTB domain can simultaneously bind PI and the ApoER2 tail. Recruitment of the Dab1 PTB domain to PI-rich regions of the plasma membrane may facilitate association with the Reelin receptor cytoplasmic tails to transduce a critical positional cue to migrating neurons.

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KW - Lipoprotein receptor

KW - Phosphoinositide

KW - Reelin signaling

KW - X-ray crystallography

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Origins of peptide selectivity and phosphoinositide binding revealed by structures of Disabled-1 PTB domain complexes

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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