Origins of Peptide Selectivity and Phosphoinositide Binding Revealed by Structures of Disabled-1 PTB Domain Complexes
Open accessAbstract
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 A 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-4,5P(2) (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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The PTB domains of ARH and DAB1 form an important structural determinant for binding LDLR family members.
“The PTB domains of the adaptor proteins ARH and DAB1 form an important structural determinant for binding LDLR family members (6, 15).”
From Distinct Functional Domains Contribute to Degradation of the Low Density Lipoprotein Receptor (LDLR) by the E3 Ubiquitin Ligase Inducible Degrader of the LDLR (IDOL) (2011) · cites this paper as [15]
The Results and Discussion (page unavailable) show that the Dab1 PTB domain binds peptides from the cytoplasmic tails of ApoER2 and VLDLR, supporting the Dab1 part of the claim. The paper aligns an ARH sequence with PTB domains and cites work on ARH–LDL receptor interaction, but the passages do not establish that ARH’s PTB-domain structure determines that binding. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSeveral residues within this helix contribute to APOER2 binding to DAB1.
“Several residues within this helix contribute to APOER2 binding to DAB1”
Analysis of the homology model of the IDOL PTB and the DAB1-APOER2 crystal structure identified a structurally conserved α-helix that forms part of a receptor-binding pocket.
“Analysis of the homology model of the IDOL PTB and the DAB1-APOER2 crystal structure (15) identified a structurally conserved ␣-helix that forms part of a receptor-binding pocket.”
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Cites
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Herz, J., & Chen, Y. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn2009 · Cited by 524 · see citing works
Self-citationBeffert, U., Weeber, E. J., Durudas, A., Qiu, S., Masiulis, I., Sweatt, J. D., Li, W.-P., Adelmann, G., Frotscher, M., Hammer, R. E., et al. (2005) · Neuron · doi:10.1016/j.neuron.2005.07.007 · Cited by 497 · see citing works
Self-citationBock, H. H., Jossin, Y., Liu, P., Förster, E., May, P., Goffinet, A. M., & Herz, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306416200 · Cited by 213 · see citing works
Self-citationDAB1 and Reelin effects on amyloid precursor protein and ApoE receptor 2 trafficking and processing
Hoe, H.-S., Tran, T. S., Matsuoka, Y., Howell, B. W., & Rebeck, G. W. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602162200 · Cited by 174 · see citing works
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D'Arcangelo, G. (2014) · Advances in Neuroscience · doi:10.1155/2014/597395 · Cited by 120 · see citing works
Canonical and non-canonical Reelin signaling
Bock, H. H., & May, P. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00166 · Cited by 107 · see citing works
Bock, H. H., Jossin, Y., May, P., Bergner, O., & Herz, J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401770200 · Cited by 102 · see citing works
Self-citationJohnson, E. B., Steffen, D. J., Lynch, K. W., & Herz, J. (2006) · Genomics · doi:10.1016/j.ygeno.2006.08.005 · Cited by 62 · see citing works
Self-citationSorrentino, V., Scheer, L., Santos, A., Reits, E., Bleijlevens, B., & Zelcer, N. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.249557 · Cited by 53 · see citing works
- Authors
- Stolt, P. C., Jeon, H., Song, H. K., Herz, J., Eck, M. J., & Blacklow, S. C.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Blacklow, Stephen C.
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2003-05
- Volume
- 11
- Issue
- 5
- Pages
- 569-579
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W1982750125
- Cited by
- 117
- References
- 1
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 3 · 2014: 3 · 2013: 4 · 2012: 8
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HL20948, HL63762)
- National Heart, Lung, and Blood Institute (HL-20948, HL-61001, HL63762, R37HL063762, R01HL061001, P01HL020948)
- National Institute of Neurological Disorders and Stroke (NS43408, R01NS043408)
- National Center for Research Resources (RR-01646, P41RR001646)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- Disabled-1, phosphotyrosine binding domain, ApoER2, Reelin signaling, phosphoinositide binding, NPXY motif, peptide selectivity, neocortex development, neuronal migration, receptor tyrosine phosphorylation, plasma membrane
- MeSH terms
- Reelin Protein, Amino Acid Sequence, Animals, Binding Sites, Humans, Molecular Sequence Data, Nerve Tissue Proteins, Peptides, Phosphatidylinositols, Protein Binding, Sequence Alignment, Protein Structure, Tertiary, Crystallography, X-Ray, Adaptor Proteins, Signal Transducing
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