A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling
Authors
Nagpal, KamalpreetPlantinga, Theo S.
Wong, Joyce
Monks, Brian G.
Gay, Nicholas J.
Netea, Mihai G.
Fitzgerald, Katherine A.
Golenbock, Douglas T.
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2009-06-11Keywords
Amino Acid SubstitutionBinding Sites
Cell Line
Cohort Studies
Computer Simulation
Female
Humans
Lipopeptides
Lipopolysaccharides
Male
Membrane Glycoproteins
Models, Molecular
Mutation, Missense
Myeloid Differentiation Factor 88
Polymorphism, Single Nucleotide
Protein Binding
Protein Structure, Tertiary
Receptors, Interleukin-1
Signal Transduction
Toll-Like Receptor 2
Toll-Like Receptor 4
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
The adapter protein MyD88 adapter-like (Mal), encoded by TIR-domain containing adapter protein (Tirap) (MIM 606252), is the most polymorphic of the five adapter proteins involved in Toll-like receptor signaling, harboring eight non-synonymous single nucleotide polymorphisms in its coding region. We screened reported mutations of Mal for activity in reporter assays to test the hypothesis that variants of Mal existed with altered signaling potential. A TIR domain variant, Mal D96N (rs8177400), was found to be inactive. In reconstituted cell lines, Mal D96N acted as a hypomorphic mutation, with impaired cytokine production and NF-kappaB activation upon lipopolysaccharide or PAM2CSK4 stimulation. Moreover, co-immunoprecipitation studies revealed that Mal D96N is unable to interact with MyD88, a prerequisite for downstream signaling to occur. Computer modeling data suggested that residue 96 resides in the MyD88 binding site, further supporting these findings. Genotyping of Mal D96N in three different cohorts suggested that it is a rare mutation. We, thus, describe a rare variant in Mal that exerts its effect via its inability to bind MyD88.Source
J Biol Chem. 2009 Sep 18;284(38):25742-8. Epub 2009 Jun 9. Link to article on publisher's siteDOI
10.1074/jbc.M109.014886Permanent Link to this Item
http://hdl.handle.net/20.500.14038/35227PubMed ID
19509286Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M109.014886