Molecular mechanism for the action of the anti-CD44 monoclonal antibody MEM-85
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11310%2F15%3A10316691" target="_blank" >RIV/00216208:11310/15:10316691 - isvavai.cz</a>
Alternative codes found
RIV/61388971:_____/15:00455882 RIV/68378050:_____/15:00455882 RIV/61388963:_____/15:00456443
Result on the web
<a href="http://dx.doi.org/10.1016/j.jsb.2015.06.005" target="_blank" >http://dx.doi.org/10.1016/j.jsb.2015.06.005</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.jsb.2015.06.005" target="_blank" >10.1016/j.jsb.2015.06.005</a>
Alternative languages
Result language
angličtina
Original language name
Molecular mechanism for the action of the anti-CD44 monoclonal antibody MEM-85
Original language description
The hyaluronate receptor CD44 plays role in cell adhesion and migration and is involved in tumor metastasis. The extracellular domain of CD44 comprises the hyaluronate-binding domain (HABD) and the membrane-proximal stem region; the short intracellular portion interacts with adaptor proteins and triggers signaling pathways. Binding of hyaluronate to CD44 HABD induces an allosteric conformational change, which results in CD44 shedding. A poorly characterized epitope in human CD44 HABD is recognized by the murine monoclonal antibody MEM-85, which cross-blocks hyaluronate binding to CD44 and also induces CD44 shedding. MEM-85 is of therapeutic interest, as it inhibits growth of lung cancer cells in murine models. In this work, we employed a combination of biophysical methods to determine the MEM-85 binding epitope in CD44 HABD and to provide detailed insight into the mechanism of MEM-85 action. In particular, we constructed a single-chain variable fragment (scFv) of MEM-85 as a tool for detailed characterization of the CD44 HABD-antibody complex and identified residues within CD44 HABD involved in the interaction with scEv MEM-85 by NMR spectroscopy and mutational analysis. In addition, we built a rigid body model of the CD44 HABD-scFv MEM-85 complex using a low-resolution structure obtained by small-angle X-ray scattering. The MEM-85 epitope is situated in the C-terminal part of CD44 HABD, rather than the hyaluronate-binding groove, and the binding of MEM-85 induces a structural reorganization similar to that induced by hyaluronate. Therefore, the mechanism of MEM-85 cross-blocking of hyaluronate binding is likely of an allosteric, relay-like nature.
Czech name
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Czech description
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Classification
Type
J<sub>x</sub> - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)
CEP classification
EB - Genetics and molecular biology
OECD FORD branch
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Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
S - Specificky vyzkum na vysokych skolach<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2015
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of Structural Biology
ISSN
1047-8477
e-ISSN
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Volume of the periodical
191
Issue of the periodical within the volume
2
Country of publishing house
US - UNITED STATES
Number of pages
10
Pages from-to
214-223
UT code for WoS article
000359096700015
EID of the result in the Scopus database
2-s2.0-84937812323