21 Turk et al Structure Reelin.pdf (5 MB)
Download fileThe structure-function relationship of a signaling-competent, dimeric Reelin fragment
journal contribution
posted on 2022-08-04, 22:06 authored by LS Turk, X Kuang, V Dal Pozzo, K Patel, M Chen, K Huynh, MJ Currie, D Mitchell, RCJ Dobson, G D'Arcangelo, W Dai, Davide ComolettiDavide ComolettiReelin operates through canonical and non-canonical pathways that mediate several aspects of brain development and function. Reelin's dimeric central fragment (CF), generated through proteolytic cleavage, is required for the lipoprotein-receptor-dependent canonical pathway activation. Here, we analyze the signaling properties of a variety of Reelin fragments and measure the differential binding affinities of monomeric and dimeric CF fragments to lipoprotein receptors to investigate the mode of canonical signal activation. We also present the cryoelectron tomography-solved dimeric structure of Reelin CF and support it using several other biophysical techniques. Our findings suggest that Reelin CF forms a covalent parallel dimer with some degree of flexibility between the two protein chains. As a result of this conformation, Reelin binds to lipoprotein receptors in a manner inaccessible to its monomeric form and is capable of stimulating canonical pathway signaling.
Funding
Collaborative Research: Structure and Function of Reelin in Brain Development | Funder: RUTGERS UNIVERSITY | Grant ID: 1755189
History
Preferred citation
Turk, L. S., Kuang, X., Dal Pozzo, V., Patel, K., Chen, M., Huynh, K., Currie, M. J., Mitchell, D., Dobson, R. C. J., D'Arcangelo, G., Dai, W. & Comoletti, D. (2021). The structure-function relationship of a signaling-competent, dimeric Reelin fragment. Structure, 29(10), 1156-1170.e6. https://doi.org/10.1016/j.str.2021.05.012Publisher DOI
Journal title
StructureVolume
29Issue
10Publication date
2021-10-07Pagination
1156-1170.e6Publisher
Elsevier BVPublication status
PublishedOnline publication date
2021-10-01ISSN
0969-2126eISSN
1878-4186Language
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AUCApoER2ReelinSAXSVLDLRcryo-ETdimerhigh-content analysisstructure-functionCryoelectron MicroscopyHEK293 CellsHumansProtein DomainsProtein MultimerizationReceptors, LDLReelin ProteinSignal Transduction1.1 Normal biological development and functioning1 Underpinning researchChemical SciencesBiological SciencesInformation and Computing SciencesBiophysics