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Mechanistic Insights Into Chromatin Recognition by the SAND Domain of Speckled Protein 110C
Lathrop, Annika
Lathrop, Annika
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Abstract
Speckled proteins (SP) are chromatin-binding proteins that transcriptionally regulate gene silencing in immune cells. Both normal and aberrant expression of SPs is correlated with immunodeficiency, inflammation, genomic instability, and viral disease. SP110C is expressed in innate and adaptive immune cells as well as non-immune cells and is essential for adaptive immune cell development and function. Loss of function mutations in SP110 are associated with a deficiency of the adaptive immune system. SP110 contains several functional domains that drive the protein’s activity, including a conserved SAND domain. SAND domains are found within several proteins linked to disease and are hypothesized to interact with DNA. However, the structure, function, and molecular interactions that drive the SAND domain’s activity have remained uncharacterized in SP110C.
Dynamic light scattering, protein modelling, and chromatographic analysis demonstrate that the SAND domain likely functions as a dimer in solution. Fluorescence anisotropy assays indicate that the SAND domain mediates DNA binding in SP110C. The SP110C-SAND domain binds undamaged dsDNA with a higher affinity than homologous damaged dsDNA, which may provide further evidence supporting the protein’s role in maintaining genomic stability. The SAND domain binding pocket has been extended to the KNWKR motif in SP110C, which may have implications for expanding the accepted binding motif of other SAND-containing proteins. These binding and structural studies serve to further the advancement of genetic and chromatin-regulatory considerations in therapies directed towards cancer, inflammation, and immune system regulation.
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2026-04-16
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Biochemistry