The Interaction between the Third Type III Domain
from Fibronectin and Anastellin Involves β‑Strand Exchange
Posted on 2017-08-17 - 21:43
Anastellin
is a small recombinant fragment derived from the extracellular
matrix protein fibronectin; it comprises the first type III (FN3)
domain without the two N-terminal β-strands. It inhibits angiogenesis,
tumor growth, and metastasis in mouse models and requires endogenous
fibronectin for its in vivo anti-angiogenic activity.
It binds to fibronectin in vitro and converts the
soluble protein to insoluble fibrils that structurally and functionally
resemble fibronectin fibrils deposited in the extracellular matrix
by cells. Anastellin binds to several FN3 domains in fibronectin,
but how it interacts with these domains and why the interactions lead
to aggregation of fibronectin are not well understood. In this work,
we investigated the interaction between anastellin and the third FN3
domain (3FN3) from fibronectin. We show that anastellin binds with
high affinity to a peptide comprising the two N-terminal β-strands
from 3FN3, and we present here the structure of the resulting complex.
The peptide and anastellin form a composite FN3 domain, with the two
N-terminal β-strands from 3FN3 bound in place of the two β-strands
that are missing in anastellin. We also demonstrate using disulfide
cross-linking that a similar interaction involving the two N-terminal
β-strands of 3FN3 occurs when intact 3FN3 binds to anastellin.
3FN3 adopts a compact globular fold in solution, and to interact with
anastellin in a manner consistent with our data, it has to open up
and expose a β-strand edge that is not accessible in the context
of the folded domain.
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Stine, Jessica
M.; Ahl, Gabriel J. H.; Schlenker, Casey; Rusnac, Domnita-Valeria; Briknarová, Klára (2017). The Interaction between the Third Type III Domain
from Fibronectin and Anastellin Involves β‑Strand Exchange. ACS Publications. Collection. https://doi.org/10.1021/acs.biochem.7b00633
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AUTHORS (5)
JS
Jessica
M. Stine
GA
Gabriel J. H. Ahl
CS
Casey Schlenker
DR
Domnita-Valeria Rusnac
KB
Klára Briknarová