9IF9

Crystal structure of the Pellino 1 FHA domain in complex with a MDC1-TQxF phosphopeptide.

Summary for 9IF9

• Entry DOI: 10.2210/pdb9if9/pdb
• Descriptor: E3 ubiquitin-protein ligase pellino homolog 1, Mediator of DNA damage checkpoint protein 1, SULFATE ION, ... (4 entities in total)
• Functional Keywords: fha, phosphopeptide binding domain, ring, e3 ligase, dna damage, dna repair, peptide binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 58374.82

Authors

Stewart, M.J.,Torres Esteban, M.,Smerdon, S.J.,Stucki, M. (deposition date: 2025-02-17, release date: 2025-03-05, Last modification date: 2025-03-26)

Primary citation

Torres Esteban, M.,Stewart, M.J.,Bragginton, E.,Meroni, A.,Pellizzari, A.,Jeanrenaud, A.,Smerdon, S.J.,Stucki, M.
MDC1 mediates Pellino recruitment to sites of DNA double-strand breaks.
Life Sci Alliance, 8:-, 2025

PubMed Abstract: Ubiquitylation is critically implicated in the recognition and repair of DNA double-strand breaks. The adaptor protein MDC1 mediates the recruitment of the key DNA damage responsive E3 ubiquitin ligase RNF8 to the break sites. It does so by directly interacting with RNF8 in a phosphorylation-dependent manner that involves the RNF8 FHA domain, thus initiating targeted chromatin ubiquitylation at the break sites. Here, we report that MDC1 also directly binds to two additional E3 ubiquitin ligases, Pellino 1 and 2, which were recently implicated in the DNA damage response. Through a combination of biochemical, biophysical and X-ray crystallographic approaches, we reveal the molecular details of the MDC1-Pellino complexes. Furthermore, we show that in mammalian cells, MDC1 mediates Pellino recruitment to sites of DNA double-strand breaks by a direct phosphorylation-dependent interaction between the two proteins. Taken together, our findings provide new molecular insights into the ubiquitylation pathways that govern genome stability maintenance.

PubMed: 40049731
DOI: 10.26508/lsa.202403074

Experimental method

X-RAY DIFFRACTION (2.55 Å)