22 Turk et al Biophys J.pdf (2.47 MB)
Download file

Structure of Reelin repeat 8 and the adjacent C-terminal region

Download (2.47 MB)
journal contribution
posted on 04.08.2022, 05:42 authored by LS Turk, MJ Currie, RCJ Dobson, Davide ComolettiDavide Comoletti
Neuronal development and function are dependent in part on the several roles of the secreted glycoprotein Reelin. Endogenous proteases process this 400 kDa, modular protein, yielding N-terminal, central, and C-terminal fragments that each have distinct roles in Reelin's function and regulation. The C-terminal fragment comprises Reelin repeat (RR) domains seven and eight, as well as a basic stretch of 32 amino acid residues termed the C-terminal region (CTR), influences Reelin signaling intensity, and has been reported to bind to Neuropilin-1, which serves as a co-receptor in the canonical Reelin signaling pathway. Here, we present a crystal structure of RR8 at 3.0 Å resolution. Analytical ultracentrifugation and small-angle x-ray scattering confirmed that RR8 is monomeric and enabled us to identify the CTR as a flexible, yet compact subdomain. We conducted structurally informed protein engineering to design a chimeric RR8 construct guided by the structural similarities with RR6. Experimental results support a mode of Reelin-receptor interaction reliant on the multiple interfaces coordinating the binding event. Structurally, RR8 resembles other individual RRs, but its structure does show discrete differences that may account for Reelin receptor specificity toward RR6.

Funding

Collaborative Research: Structure and Function of Reelin in Brain Development | Funder: RUTGERS UNIVERSITY | Grant ID: 1755189

History

Preferred citation

Turk, L. S., Currie, M. J., Dobson, R. C. J. & Comoletti, D. (2022). Structure of Reelin repeat 8 and the adjacent C-terminal region. Biophysical Journal, 121(13), 2526-2537. https://doi.org/10.1016/j.bpj.2022.06.002

Journal title

Biophysical Journal

Volume

121

Issue

13

Publication date

05/07/2022

Pagination

2526-2537

Publisher

Elsevier BV

Publication status

Published

Online publication date

01/07/2022

ISSN

0006-3495

eISSN

1542-0086

Language

en