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The SLE variant Ala71Thr of BLK severely decreases protein abundance and binding to BANK1 through impairment of the SH3 domain function.

dc.contributor.authorDíaz-Barreiro, A
dc.contributor.authorBernal-Quirós, M
dc.contributor.authorGeorg, I
dc.contributor.authorMarañón, C
dc.contributor.authorAlarcón-Riquelme, M E
dc.contributor.authorCastillejo-López, C
dc.date.accessioned2023-01-25T08:30:47Z
dc.date.available2023-01-25T08:30:47Z
dc.date.issued2016-01-28
dc.description.abstractThe B-lymphocyte kinase (BLK) gene is associated genetically with several human autoimmune diseases including systemic lupus erythematosus. We recently described that the genetic risk is given by two haplotypes: one covering several strongly linked single-nucleotide polymorphisms within the promoter of the gene that correlated with low transcript levels, and a second haplotype that includes a rare nonsynonymous variant (Ala71Thr). Here we show that this variant, located within the BLK SH3 domain, is a major determinant of protein levels. In vitro analyses show that the 71Thr isoform is hyperphosphorylated and promotes kinase activation. As a consequence, BLK is ubiquitinated, its proteasomal degradation enhanced and the average life of the protein is reduced by half. Altogether, these findings suggest that an intrinsic autoregulatory mechanism previously unappreciated in BLK is disrupted by the 71Thr substitution. Because the SH3 domain is also involved in protein interactions, we sought for differences between the two isoforms in trafficking and binding to protein partners. We found that binding of the 71Thr variant to the adaptor protein BANK1 is severely reduced. Our study provides new insights on the intrinsic regulation of BLK activation and highlights the dominant role of its SH3 domain in BANK1 binding.
dc.identifier.doi10.1038/gene.2016.1
dc.identifier.essn1476-5470
dc.identifier.pmid26821283
dc.identifier.urihttp://hdl.handle.net/10668/9787
dc.issue.number2
dc.journal.titleGenes and immunity
dc.journal.titleabbreviationGenes Immun
dc.language.isoen
dc.organizationCentro Pfizer-Universidad de Granada-Junta de Andalucía de Genómica e Investigación Oncológica-GENYO
dc.page.number128-38
dc.pubmedtypeJournal Article
dc.pubmedtypeResearch Support, N.I.H., Extramural
dc.pubmedtypeResearch Support, Non-U.S. Gov't
dc.subject.meshAdaptor Proteins, Signal Transducing
dc.subject.meshAmino Acid Sequence
dc.subject.meshAmino Acid Substitution
dc.subject.meshB-Lymphocytes
dc.subject.meshBinding Sites
dc.subject.meshCell Line, Tumor
dc.subject.meshGene Expression
dc.subject.meshHalf-Life
dc.subject.meshHaplotypes
dc.subject.meshHumans
dc.subject.meshLupus Erythematosus, Systemic
dc.subject.meshMembrane Proteins
dc.subject.meshModels, Molecular
dc.subject.meshMolecular Sequence Data
dc.subject.meshMutation
dc.subject.meshPromoter Regions, Genetic
dc.subject.meshProteasome Endopeptidase Complex
dc.subject.meshProtein Binding
dc.subject.meshProtein Isoforms
dc.subject.meshProteolysis
dc.subject.meshSequence Alignment
dc.subject.meshUbiquitination
dc.subject.meshsrc-Family Kinases
dc.titleThe SLE variant Ala71Thr of BLK severely decreases protein abundance and binding to BANK1 through impairment of the SH3 domain function.
dc.typeresearch article
dc.volume.number17
dspace.entity.typePublication

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