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@ARTICLE{Gudez:580693,
author = {Guédez, Gabriela and Loers, Gabriele and Jeffries, Cy M.
and Kozak, Sandra and Meijers, Rob and Svergun, Dmitri I.
and Schachner, Melitta and Loew, Christian},
title = {{X}‐ray structure and function of fibronectin domains two
and three of the neural cell adhesion molecule {L}1},
journal = {The FASEB journal},
volume = {37},
number = {3},
issn = {0892-6638},
address = {Hoboken, NJ},
publisher = {Wiley},
reportid = {PUBDB-2023-01383},
pages = {e22823},
year = {2023},
abstract = {The cell adhesion molecule L1 (L1CAM, L1 in short) plays
crucial roles during neural development, regeneration after
injury, synapse formation, synaptic plasticity and tumor
cell migration. L1 belongs to the immunoglobulin superfamily
and comprises in its extracellular part six immunoglobulin
(Ig)-like domains and five fibronectin type III homologous
repeats (FNs). The second Ig-like domain has been validated
for self- (so-called homophilic) binding between cells.
Antibodies against this domain inhibit neuronal migration in
vitro and in vivo. The fibronectin type III homologous
repeats FN2 and FN3 bind small molecule agonistic L1
mimetics and contribute to signal transduction. FN3 has a
stretch of 25 amino acids that can be triggered with a
monoclonal antibody, or the L1 mimetics, to enhance neurite
outgrowth and neuronal cell migration in vitro and in vivo.
To correlate the structural features of these FNs with
function, we determined a high-resolution crystal structure
of a FN2FN3 fragment, which is functionally active in
cerebellar granule cells and binds several mimetics. The
structure illustrates that both domains are connected by a
short linker sequence allowing a flexible and largely
independent organization of both domains. This becomes
further evident by comparing the X-ray crystal structure
with models derived from Small-Angle X-ray Scattering (SAXS)
data for FN2FN3 in solution. Based on the X-ray crystal
structure, we identified five glycosylation sites which we
believe are crucial for folding and stability of these
domains. Our study signifies an advance in the understanding
of structure–functional relationships of L1.},
cin = {EMBL-User / EMBL / CSSB-EMBL / CSSB-EMBL-CL},
ddc = {570},
cid = {I:(DE-H253)EMBL-User-20120814 / I:(DE-H253)EMBL-20120731 /
I:(DE-H253)CSSB-EMBL-20141216 /
I:(DE-H253)CSSB-EMBL-CL-20210806},
pnm = {6G3 - PETRA III (DESY) (POF4-6G3)},
pid = {G:(DE-HGF)POF4-6G3},
experiment = {EXP:(DE-H253)P-P12-20150101 / EXP:(DE-H253)P-P13-20150101 /
EXP:(DE-H253)P-P14-20150101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:36809668},
UT = {WOS:000936837500001},
doi = {10.1096/fj.202201511R},
url = {https://bib-pubdb1.desy.de/record/580693},
}