eprintid: 19369
rev_number: 31
eprint_status: archive
userid: 1589
dir: disk0/00/01/93/69
datestamp: 2015-12-01 13:48:44
lastmod: 2024-07-17 05:19:58
status_changed: 2015-12-01 13:48:44
type: article
metadata_visibility: show
creators_name: Kumar, Sumit
creators_name: Žigman, Mihaela
creators_name: Patel, Trushar R.
creators_name: Trageser, Benjamin
creators_name: Gross, Julia C.
creators_name: Rahm, Karolin
creators_name: Boutros, Michael
creators_name: Gradl, Dietmar
creators_name: Steinbeisser, Herbert
creators_name: Holstein, Thomas
creators_name: Stetefeld, Jörg
creators_name: Özbek, Suat
title: Molecular dissection of Wnt3a-Frizzled8 interaction reveals essential and modulatory determinants of Wnt signaling activity
subjects: ddc-570
divisions: i-63600
divisions: i-721000
divisions: i-911500
abstract: Background: Wnt proteins are a family of secreted signaling molecules that regulate key developmental processes in metazoans. The molecular basis of Wnt binding to Frizzled and LRP5/6 co-receptors has long been unknown due to the lack of structural data on Wnt ligands. Only recently, the crystal structure of the Wnt8-Frizzled8-cysteine-rich-domain (CRD) complex was solved, but the significance of interaction sites that influence Wnt signaling has not been assessed.   Results: Here, we present an extensive structure-function analysis of mouse Wnt3a in vitro and in vivo. We provide evidence for the essential role of serine 209, glycine 210 (site 1) and tryptophan 333 (site 2) in Fz binding. Importantly, we discovered that valine 337 in the site 2 binding loop is critical for signaling without contributing to binding. Mutations in the presumptive second CRD binding site (site 3) partly abolished Wnt binding. Intriguingly, most site 3 mutations increased Wnt signaling, probably by inhibiting Wnt-CRD oligomerization. In accordance, increasing amounts of soluble Frizzled8-CRD protein modulated Wnt3a signaling in a biphasic manner.   Conclusions: We propose a concentration-dependent switch in Wnt-CRD complex formation from an inactive aggregation state to an activated high mobility state as a possible modulatory mechanism in Wnt signaling gradients.  
date: 2014
publisher: Springer
id_scheme: DOI
official_url: http://dx.doi.org/10.1186/1741-7007-12-44
ppn_swb: 1656045826
own_urn: urn:nbn:de:bsz:16-heidok-193696
language: eng
bibsort: KUMARSUMITMOLECULARD2014
full_text_status: public
publication: BMC biology
volume: 12
number: 44
place_of_pub: Berlin ; Heidelberg
pagerange: 1-16
issn: 1741-7007
citation:   Kumar, Sumit ; Žigman, Mihaela ; Patel, Trushar R. ; Trageser, Benjamin ; Gross, Julia C. ; Rahm, Karolin ; Boutros, Michael ; Gradl, Dietmar ; Steinbeisser, Herbert ; Holstein, Thomas ; Stetefeld, Jörg ; Özbek, Suat  (2014) Molecular dissection of Wnt3a-Frizzled8 interaction reveals essential and modulatory determinants of Wnt signaling activity.  BMC biology, 12 (44).  pp. 1-16.  ISSN 1741-7007     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/19369/1/12915_2014_Article_774.pdf