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The structure-function relationship of a signaling-competent, dimeric Reelin fragment

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posted on 04.08.2022, 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 Comoletti
Reelin 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.2021.05.012

Journal title

Structure

Volume

29

Issue

10

Publication date

07/10/2021

Pagination

1156-1170.e6

Publisher

Elsevier BV

Publication status

Published

Online publication date

01/10/2021

ISSN

0969-2126

eISSN

1878-4186

Language

en