Bivalent Copper Ions Promote Fibrillar Aggregation of KCTD1 and Induce Cytotoxicity

Abstract

Potassium channel tetramerization domain containing 1 (KCTD1) family members have a BTB/POZ domain, which can facilitate protein-protein interactions involved in the regulation of different signaling pathways. KCTD proteins have potential Zn2+/Cu2+ binding sites with currently unknown structural and functional roles. We investigated potential Cu2+-specific effects on KCTD1 using circular dichroism, turbidity measurement, fluorescent dye binding, proteinase K (PK) digestion, cell proliferation and apoptosis assays. These experiments indicate that the KCTD1 secondary structure assumes greater β-sheet content and the proteins aggregate into a PK-resistant form under 20 μM Cu2+, and this β-sheet-rich aggregation with Cu2+ promotes fibril formation, which results in increased cell toxicity by apoptosis. Our results reveal a novel role for Cu2+ in determining the structure and function of KCTD1.