Abstract
Several proteins other than the frizzled receptors (Fzd) and the secreted Frizzled-related proteins (sFRP) contain Fzd-type cysteine-rich domains (CRD). We have termed these domains “putative Fzd-type CRDs”, as the relevance of Wnt signalling in the majority of these is unknown; the RORs, an exception to this, are well known for mediating non-canonical Wnt signalling. In this study, we have predicted the likely binding affinity of all Wnts for all putative Fzd-type CRDs. We applied both our previously determined Wnt‒Fzd CRD binding affinity prediction model, as well as a newly devised model wherein the lipid term was forced to contribute favourably to the predicted binding energy. The results obtained from our new model indicate that certain putative Fzd CRDs are much more likely to bind Wnts, in some cases exhibiting selectivity for specific Wnts. The results of this study inform the investigation of Wnt signalling modulation beyond Fzds and sFRPs.
Highlights
The Wnt signalling pathway is an evolutionarily conserved signalling cascade that dictates many aspects of development and cell fate. It is initiated through the extracellular binding of Wnt ligands to membrane receptor complexes [1]. These signalling cascades are classified as canonical (β-catenin dependent) or non-canonical (β-catenin independent). β-catenin-dependent signalling is initiated following Wnt ligand binding to the cysteine-rich domain (CRD) of Frizzled (Fzd) receptors to recruit the low-density lipoprotein receptor 5/6 (LRP5/6) [2]
The LRP/Fzd receptor complex transduces signals to a cytoplasmic protein complex composed of glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), Axin and adenomatous polyposis coli (APC)
Wnt signalling is known to be negatively regulated by sequestration of Wnt ligands by endogenous secreted Frizzled-related proteins [6,7], which carry a Fzd-type CRD thought to mediate this process
Summary
The Wnt signalling pathway is an evolutionarily conserved signalling cascade that dictates many aspects of development and cell fate It is initiated through the extracellular binding of Wnt ligands to membrane receptor complexes [1]. A peculiar feature of this model is that the coefficient of the lipid-protein term in our model, which is derived from the Prime MM-GB/SA van der Waals component, is negative; since the values calculated by MMGBSA dG vdW are typically negative, the net result is that this term contributes positively—and unfavourably—to the predicted binding energy This is at odds with the majority of experimental findings that suggest the lipid is essential for Wnt signalling [4,32], one recent study suggests that Wnt lipidation is not essential for Wnt signalling in specific contexts [33]. We have aimed to estimate the binding affinities for all human Wnts with all human proteIinnsthbisesatruindgy, pwuetahtaivvee aFizmdedCRtoDess.tiWmaeteapthpelibedindoiunrgparffievniiotiuesslfyordaelrlivheudmaWnnWt‒nFtzsdwCitRhDallbhinudminang pafrfointeiitnyspbreedaricintigonpmutoadtievle, aFszwd eCllRaDs sd.evWeeloappepdlaiendeowubr ipnrdeivnigouafsfliynidtyerpivreeddicWtionnt-FmzoddCelR, fDorbciinngditnhge aliffipindi‒tpyrporteedinicctoionntrmiboudtieoln, aisnwtheellmasoddeevl etolobpeedfaavonuerwabblien,dthinugs abffietnteirtyapccroeudnicttiinogn fmorotdheel,rfoolrecionfgWthnet lliippiidd-aptiroonteiinn cboinndtriinbgu.tWionhiilne tthhee mneowdeml toodbeel faafvfoorudrsabalne,itnhcuresabseetdteerraroccrocuonmtipnagrefodr ttohethreolpe roefvWiounst lmipoiddaetli,otnheinmbainjodriintyg.oWf hbiinledtihnegnaefwfinmitoiedselfoarffoWrdnst‒aFnzidncarneadseWdnetr‒rosFrRcoPminptaerreadcttioonthseaprreevpiroeudsicmteoddetol, tohcecumr aijnorsiitmy iolafrbrinandginegs taoffitnhietipesrefvoirouWsnmt-oFdzdel.aAndppWlynitn-gsFtRhPe ninetweramcotidoenlstaoreesptirmedaitceteWdntot‒opcuctuatrivine sFizmdilbarinrdainnggesatfofinthiteiepsreimvipouliscamteosdseel.vAerpapl loyfintghetshee innewprmevoidoeulstlyo eusntiemxpatleorWedntr-opluetsatiinveefFfzedctibnigndainndg amffiondiutileastiinmgpWlicnattseisgsneavlleirnagl.oTfhteheresesuinltsphreevreiowuislllyinufnoerxmplionrveedstrioglaetsioinnseofffeWctinntgsaignndamllinodgumlaotdinuglaWtionnt sbiegynoanlldinWg.nTth‒Fezrdesaunltds Whenret‒wsFilRl Pinifnotremraicntvioenssti.gations of Wnt signalling modulation beyond Wnt-Fzd and Wnt-sFRP interactions
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