A BTB extension and ion-binding domain contribute to the pentameric structure and TFAP2A binding of KCTD1

Preprint

KCTD family proteins typically assemble into Cullin-RING E3 ligases. KCTD1 is an atypical member that functions instead as a transcriptional repressor. Mutations in KCTD1 cause developmental abnormalities and kidney fibrosis in scalp-ear-nipple syndrome. Here, we present unexpected mechanistic insights from the structure of full-length KCTD1. Disease-causing mutation P20S maps to an unrecognized extension of the BTB domain that contributes both to its pentameric structure and TFAP2A binding. The C-terminal domain (CTD) shares its fold and pentameric assembly with the protein GFRP despite lacking discernible sequence similarity. Most surprisingly, the KCTD1 CTD establishes a central channel occupied by alternating sodium and iodide ions that restrict TFAP2A dissociation. The elucidation of the structure redefines the KCTD family BTB domain fold and identifies an unexpected ion pore for future study of KCTD1’s function in the ectoderm, neural crest and kidney.

Authors: Pinkas, DM; Bufton, JC; Hunt, AE; Manning, CE; Richardson, W

• Publication status: Published
• Peer review status: Not peer reviewed
• Preprint server: bioRxiv
• Publication date: 2024-06-14
• DOI: 10.1101/2024.06.14.599093
• EISSN: 2692-8205
• Language: English
• Keywords: beta-propeller; X-ray crystallography; BTB domain; ion channel; scalp-ear-nipple syndrome; pentamer; Cullin-RING ligase; Cullin3; TFAP2; KCTD