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Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex

Kenneth Verstraete UGent, Gonzalez Vandriessche, Mariska Januar UGent, Jonathan Elegheert UGent, Alexander V Shkumatov, Ambroise Desfosses, Kathleen Van Craenenbroeck UGent, Dmitri I Svergun, Irina Gutsche and Bjorn Vergauwen UGent, et al. (2011) BLOOD. 118(1). p.60-68
abstract
The class III receptor tyrosine kinase (RTKIII) Fms-like tyrosine kinase receptor 3 (Flt3) and its cytokine ligand (FL) play central roles in hematopoiesis and the immune system, by establishing signaling cascades crucial for the development and homeostasis of hematopoietic progenitors and antigen-presenting dendritic cells. However, Flt3 is also one of the most frequently mutated receptors in hematologic malignancies and is currently a major prognostic factor and clinical target for acute myeloid leukemia. Here, we report the structural basis for the Flt3 ligand-receptor complex and unveil an unanticipated extracellular assembly unlike any other RTKIII/V complex characterized to date. FL induces dimerization of Flt3 via a remarkably compact binding epitope localized at the tip of extracellular domain 3 of Flt3, and it invokes a ternary complex devoid of homotypic receptor interactions. Comparisons of Flt3 with homologous receptors and available mutagenesis data for FL have allowed us to rationalize the unique features of the Flt3 extracellular assembly. Furthermore, thermodynamic dissection of complex formation points to a pronounced enthalpically driven binding event coupled to an entropic penalty. Together, our data suggest that the high-affinity Flt3: FL complex is driven in part by a single preformed binding epitope on FL reminiscent of a "lock-and-key" binding mode, thereby setting the stage for antagonist design.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
ACUTE MYELOID-LEUKEMIA, DENDRITIC CELL-DEVELOPMENT, RECEPTOR TYROSINE KINASES, JUXTAMEMBRANE DOMAIN, STEM-CELL, LIGAND, ACTIVATION, CYTOKINE, IDENTIFICATION, EXPRESSION
journal title
BLOOD
Blood
volume
118
issue
1
pages
60 - 68
Web of Science type
Article
Web of Science id
000292505900012
JCR category
HEMATOLOGY
JCR impact factor
9.898 (2011)
JCR rank
2/68 (2011)
JCR quartile
1 (2011)
ISSN
0006-4971
DOI
10.1182/blood-2011-01-329532
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2103110
handle
http://hdl.handle.net/1854/LU-2103110
date created
2012-05-09 20:49:46
date last changed
2012-05-10 10:58:45
@article{2103110,
  abstract     = {The class III receptor tyrosine kinase (RTKIII) Fms-like tyrosine kinase receptor 3 (Flt3) and its cytokine ligand (FL) play central roles in hematopoiesis and the immune system, by establishing signaling cascades crucial for the development and homeostasis of hematopoietic progenitors and antigen-presenting dendritic cells. However, Flt3 is also one of the most frequently mutated receptors in hematologic malignancies and is currently a major prognostic factor and clinical target for acute myeloid leukemia. Here, we report the structural basis for the Flt3 ligand-receptor complex and unveil an unanticipated extracellular assembly unlike any other RTKIII/V complex characterized to date. FL induces dimerization of Flt3 via a remarkably compact binding epitope localized at the tip of extracellular domain 3 of Flt3, and it invokes a ternary complex devoid of homotypic receptor interactions. Comparisons of Flt3 with homologous receptors and available mutagenesis data for FL have allowed us to rationalize the unique features of the Flt3 extracellular assembly. Furthermore, thermodynamic dissection of complex formation points to a pronounced enthalpically driven binding event coupled to an entropic penalty. Together, our data suggest that the high-affinity Flt3: FL complex is driven in part by a single preformed binding epitope on FL reminiscent of a {\textacutedbl}lock-and-key{\textacutedbl} binding mode, thereby setting the stage for antagonist design.},
  author       = {Verstraete, Kenneth and Vandriessche, Gonzalez and Januar, Mariska and Elegheert, Jonathan and Shkumatov, Alexander V and Desfosses, Ambroise and Van Craenenbroeck, Kathleen and Svergun, Dmitri I and Gutsche, Irina and Vergauwen, Bjorn and Savvides, Savvas},
  issn         = {0006-4971},
  journal      = {BLOOD},
  keyword      = {ACUTE MYELOID-LEUKEMIA,DENDRITIC CELL-DEVELOPMENT,RECEPTOR TYROSINE KINASES,JUXTAMEMBRANE DOMAIN,STEM-CELL,LIGAND,ACTIVATION,CYTOKINE,IDENTIFICATION,EXPRESSION},
  language     = {eng},
  number       = {1},
  pages        = {60--68},
  title        = {Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex},
  url          = {http://dx.doi.org/10.1182/blood-2011-01-329532},
  volume       = {118},
  year         = {2011},
}

Chicago
Verstraete, Kenneth, Gonzalez Vandriessche, Mariska Januar, Jonathan Elegheert, Alexander V Shkumatov, Ambroise Desfosses, Kathleen Van Craenenbroeck, et al. 2011. “Structural Insights into the Extracellular Assembly of the Hematopoietic Flt3 Signaling Complex.” Blood 118 (1): 60–68.
APA
Verstraete, Kenneth, Vandriessche, G., Januar, M., Elegheert, J., Shkumatov, A. V., Desfosses, A., Van Craenenbroeck, K., et al. (2011). Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex. BLOOD, 118(1), 60–68.
Vancouver
1.
Verstraete K, Vandriessche G, Januar M, Elegheert J, Shkumatov AV, Desfosses A, et al. Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex. BLOOD. 2011;118(1):60–8.
MLA
Verstraete, Kenneth, Gonzalez Vandriessche, Mariska Januar, et al. “Structural Insights into the Extracellular Assembly of the Hematopoietic Flt3 Signaling Complex.” BLOOD 118.1 (2011): 60–68. Print.