3U3Z

Structure of human microcephalin (MCPH1) tandem BRCT domains in complex with an H2A.X peptide phosphorylated at Ser139 and Tyr142

Summary for 3U3Z

• Entry DOI: 10.2210/pdb3u3z/pdb
• Descriptor: Microcephalin, Histone H2A.X peptide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: dna repair, cell cycle regulation, cell cycle
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm, cytoskeleton, centrosome: Q8NEM0
• Total number of polymer chains: 2
• Total formula weight: 22819.21

Authors

Singh, N.,Thompson, J.R.,Heroux, A.,Mer, G. (deposition date: 2011-10-06, release date: 2012-07-25, Last modification date: 2024-10-30)

Primary citation

Singh, N.,Basnet, H.,Wiltshire, T.D.,Mohammad, D.H.,Thompson, J.R.,Heroux, A.,Botuyan, M.V.,Yaffe, M.B.,Couch, F.J.,Rosenfeld, M.G.,Mer, G.
Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1.
Proc.Natl.Acad.Sci.USA, 109:14381-14386, 2012

PubMed Abstract: Tyr142, the C-terminal amino acid of histone variant H2A.X is phosphorylated by WSTF (Williams-Beuren syndrome transcription factor), a component of the WICH complex (WSTF-ISWI chromatin-remodeling complex), under basal conditions in the cell. In response to DNA double-strand breaks (DSBs), H2A.X is instantaneously phosphorylated at Ser139 by the kinases ATM and ATR and is progressively dephosphorylated at Tyr142 by the Eya1 and Eya3 tyrosine phosphatases, resulting in a temporal switch from a postulated diphosphorylated (pSer139, pTyr142) to monophosphorylated (pSer139) H2A.X state. How mediator proteins interpret these two signals remains a question of fundamental interest. We provide structural, biochemical, and cellular evidence that Microcephalin (MCPH1), an early DNA damage response protein, can read both modifications via its tandem BRCA1 C-terminal (BRCT) domains, thereby emerging as a versatile sensor of H2A.X phosphorylation marks. We show that MCPH1 recruitment to sites of DNA damage is linked to both states of H2A.X.

PubMed: 22908299
DOI: 10.1073/pnas.1212366109

Experimental method

X-RAY DIFFRACTION (1.5 Å)