4D2H

Crystal structure of the tetramerisation domain of human CtIP

Summary for 4D2H

• Entry DOI: 10.2210/pdb4d2h/pdb
• Descriptor: RBBP8, SULFATE ION (3 entities in total)
• Functional Keywords: gene regulation, ctip/rbbp8, double-strand dna break repair, dna-end resection, gene conversion, homologous recombination
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 8
• Total formula weight: 37442.76

Authors

Davies, O.R.,Sun, M.,Pellegrini, L. (deposition date: 2014-05-09, release date: 2015-01-14, Last modification date: 2024-05-08)

Primary citation

Davies, O.R.,Forment, J.V.,Sun, M.,Belotserkovskaya, R.,Coates, J.,Galanty, Y.,Demir, M.,Morton, C.R.,Rzechorzek, N.J.,Jackson, S.P.,Pellegrini, L.
Ctip Tetramer Assembly is Required for DNA-End Resection and Repair.
Nat.Struct.Mol.Biol., 22:150-, 2015

PubMed Abstract: Mammalian CtIP protein has major roles in DNA double-strand break (DSB) repair. Although it is well established that CtIP promotes DNA-end resection in preparation for homology-dependent DSB repair, the molecular basis for this function has remained unknown. Here we show by biophysical and X-ray crystallographic analyses that the N-terminal domain of human CtIP exists as a stable homotetramer. Tetramerization results from interlocking interactions between the N-terminal extensions of CtIP's coiled-coil region, which lead to a 'dimer-of-dimers' architecture. Through interrogation of the CtIP structure, we identify a point mutation that abolishes tetramerization of the N-terminal domain while preserving dimerization in vitro. Notably, we establish that this mutation abrogates CtIP oligomer assembly in cells, thus leading to strong defects in DNA-end resection and gene conversion. These findings indicate that the CtIP tetramer architecture described here is essential for effective DSB repair by homologous recombination.

PubMed: 25558984
DOI: 10.1038/NSMB.2937

Experimental method

X-RAY DIFFRACTION (1.9 Å)