Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl-ester lipase gene (CEL-MODY): a protein misfolding disease
2011 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 40, 34593-34605 p.Article in journal (Refereed) Published
CEL-MODY, diabetes with pancreatic lipomatosis and exocrine dysfunction, is due to dominant frame-shift mutations in the acinar cell carboxyl-ester lipase gene (CEL). As Cel knock-out mice do not express the phenotype and the mutant protein has an altered, intrinsically disordered tandem repeat domain, we hypothesized that the disease mechanism might involve a negative effect of the mutant protein. In silico analysis showed that the pI of the tandem repeat was markedly increased from pH 3.3 in wild-type (WT) to 11.8 in mutant (MUT) human CEL. By stably over-expressing CEL-WT and CEL-MUT in HEK293 cells, we found similar glycosylation, ubiquitination, constitutive secretion and quality control of the two proteins. The CEL-MUT protein demonstrated, however, a high propensity to form aggregates found intracellularly and extracellularly. Different physico-chemical properties of the intrinsically disordered tandem repeat domains of WT and MUT proteins may contribute to different short-range and long-range interactions with the globular core domain and other macromolecules, including cell membranes. Thus, we propose that CEL-MODY is a protein misfolding disease caused by a negative gain-of-function effect of the mutant proteins in pancreatic tissues.
Place, publisher, year, edition, pages
Bethesda, Md.: American Society for Biochemistry and Molecular Biology , 2011. Vol. 286, no 40, 34593-34605 p.
Diabetes, ER stress, Genetic diseases, Metabolic diseases, Protein secretion, Protein stability, MODY, aggregation, carboxyl-ester lipase, proteopathy
Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:umu:diva-45846DOI: 10.1074/jbc.M111.222679PubMedID: 21784842OAI: oai:DiVA.org:umu-45846DiVA: diva2:435376