Linked Life Data

17276019

Source:http://linkedlifedata.com/resource/pubmed/id/17276019

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1-2
pubmed:dateCreated
2007-3-12
pubmed:abstractText
A single point mutation (G to T) in the low-density lipoprotein receptor related protein 5 (LRP5) gene results in a glycine to valine amino acid change (G171V) and is responsible for an autosomal dominant high bone mass trait (HBM) in two independent kindreds. LRP5 acts as a co-receptor to Wnts with Frizzled family members and transduces Wnt-canonical signals which can be antagonized by LRP5 ligand, Dickkopf 1 (Dkk1). In the presence of Wnt1, LRP5 or the HBM variant (LRP5-G171V) induces beta-catenin nuclear translocation and activates T cell factor (TCF)-luciferase reporter activity. HBM variant suppresses Dkk1 function and this results in reduced inhibition of TCF activity as compared to that with LRP5. Structural analysis of LRP5 revealed that the HBM mutation lies in the 4th blade of the first beta-propeller domain. To elucidate the functional significance and consequence of the LRP5-G171V mutation in vitro, we took a structure-based approach to design 15 specific LRP5 point mutations. These included (a) substitutions at the G171 in blade 4, (b) mutations in blades 2-6 of beta-propeller 1, and (c) mutations in beta-propellers 2, 3 and 4. Here we show that substitutions of glycine at 171 to K, F, I and Q also resulted in HBM-like activity in the presence of Wnt1 and Dkk1. This indicates the importance of the G171 site rather than the effect of specific amino acid modification to LRP5 receptor function. Interestingly, G171 equivalent residue mutations in other blades of beta-propeller 1 (A65V, S127V, L200V, A214V and M282V) resulted in LRP5-G171V-like block of Dkk1 function. However G171V type mutations in other beta-propellers of LRP5 did not result in resistance to Dkk1 function. These results indicate the importance of LRP5 beta-propeller 1 for Dkk1 function and Wnt signaling. These data and additional comparative structural analysis of the LRP5 family member LDLR suggest a potential functional role of the first beta-propeller domain through intramolecular interaction with other domains of LRP5 wherein Dkk1 can bind. Such studies may also lead to a better understanding of the mechanisms underlying the reduced function of Dkk1-like inhibitory ligands of LRP5 with HBM-like mutations and its relationship to increased bone density phenotypes.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0378-1119
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
391
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
103-12
pubmed:meshHeading
pubmed-meshheading:17276019-Autoantigens, pubmed-meshheading:17276019-Cell Line, Tumor, pubmed-meshheading:17276019-Cell Nucleus, pubmed-meshheading:17276019-Humans, pubmed-meshheading:17276019-Intercellular Signaling Peptides and Proteins, pubmed-meshheading:17276019-Luciferases, pubmed-meshheading:17276019-Models, Molecular, pubmed-meshheading:17276019-Mutation, pubmed-meshheading:17276019-Mutation, Missense, pubmed-meshheading:17276019-Protein Structure, Tertiary, pubmed-meshheading:17276019-Protein Transport, pubmed-meshheading:17276019-Ribonucleoproteins, pubmed-meshheading:17276019-Signal Transduction, pubmed-meshheading:17276019-Structure-Activity Relationship, pubmed-meshheading:17276019-TCF Transcription Factors, pubmed-meshheading:17276019-Wnt Proteins, pubmed-meshheading:17276019-beta Catenin
pubmed:year
2007
pubmed:articleTitle
Structure-based mutation analysis shows the importance of LRP5 beta-propeller 1 in modulating Dkk1-mediated inhibition of Wnt signaling.
pubmed:affiliation
Women's Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. bhatb@wyeth.com
pubmed:publicationType
Journal Article