9FOI

Structure of human KCTD1

Summary for 9FOI

• Entry DOI: 10.2210/pdb9foi/pdb
• Descriptor: BTB/POZ domain-containing protein KCTD1, IODIDE ION, SODIUM ION, ... (6 entities in total)
• Functional Keywords: kctd1, potassium channel tetramerization domain containing 1, btb, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 148610.61

Authors

Pinkas, D.M.,Richardson, W.,Bufton, J.C.,Hunt, A.E.,Manning, C.E.,Shrestha, L.,Borkowska, O.,Pike, A.C.W.,Burgess-Brown, N.A.,Bullock, A.N. (deposition date: 2024-06-11, release date: 2025-06-25)

Primary citation

Pinkas, D.M.,Bufton, J.C.,Hunt, A.E.,Manning, C.E.,Richardson, W.,Bullock, A.N.
A BTB extension and ion-binding domain contribute to the pentameric structure and TFAP2A binding of KCTD1.
Structure, 32:1586-1593.e4, 2024

PubMed Abstract: 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 human KCTD1. Disease-causing mutation P20S maps to an unrecognized extension of the BTB domain that contributes to both its pentameric structure and TFAP2A binding. The C-terminal domain (CTD) shares its fold and pentameric assembly with the GTP cyclohydrolase I feedback regulatory 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 KCTD1 BTB domain fold and identifies an unexpected ion-binding site for future study of KCTD1's function in the ectoderm, neural crest, and kidney.

PubMed: 39191250
DOI: 10.1016/j.str.2024.07.023

Experimental method

X-RAY DIFFRACTION (2.71 Å)