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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.
Díaz-Barreiro, A; Bernal-Quirós, M; Georg, I; Marañón, C; Alarcón-Riquelme, M E; Castillejo-López, C.
Affiliation
  • Díaz-Barreiro A; Area of Medical Genomics, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, PTS, Granada, Spain.
  • Bernal-Quirós M; Area of Medical Genomics, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, PTS, Granada, Spain.
  • Georg I; Area of Medical Genomics, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, PTS, Granada, Spain.
  • Marañón C; Area of Medical Genomics, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, PTS, Granada, Spain.
  • Alarcón-Riquelme ME; Area of Medical Genomics, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, PTS, Granada, Spain.
  • Castillejo-López C; Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Genes Immun ; 17(2): 128-38, 2016 Mar.
Article in En | MEDLINE | ID: mdl-26821283
ABSTRACT
The 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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Src-Family Kinases / Amino Acid Substitution / Adaptor Proteins, Signal Transducing / Lupus Erythematosus, Systemic / Membrane Proteins / Mutation Type of study: Prognostic_studies Limits: Humans Language: En Journal: Genes Immun Journal subject: ALERGIA E IMUNOLOGIA / BIOLOGIA MOLECULAR Year: 2016 Document type: Article Affiliation country: España

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Src-Family Kinases / Amino Acid Substitution / Adaptor Proteins, Signal Transducing / Lupus Erythematosus, Systemic / Membrane Proteins / Mutation Type of study: Prognostic_studies Limits: Humans Language: En Journal: Genes Immun Journal subject: ALERGIA E IMUNOLOGIA / BIOLOGIA MOLECULAR Year: 2016 Document type: Article Affiliation country: España