8bhy
From Proteopedia
DNA-PK Ku80 mediated dimer bound to PAXX and XLF
Structural highlights
DiseaseNHEJ1_HUMAN Defects in NHEJ1 are the cause of severe combined immunodeficiency due to NHEJ1 deficiency (NHEJ1-SCID) [MIM:611291; also known as autosomal recessive T-cell-negative, B-cell-negative, NK cell-positive, severe combined immunodeficiency with microcephaly, growth retardation and sensitivity to ionizing radiation or NHEJ1 syndrome. SCID refers to a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia and low or absent antibody levels. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. NHEJ1-SCID is characterized by a profound T- and B-lymphocytopenia associated with increased cellular sensitivity to ionizing radiation, microcephaly and growth retardation. Some patients may manifest SCID with sensitivity to ionizing radiation without microcephaly and mild growth retardation, probably due to hypomorphic NHEJ1 mutations.[1] [2] [3] [4] Note=A chromosomal aberration involving NHEJ1 is found in a patient with polymicrogyria. Translocation t(2;7)(q35;p22).[5] FunctionNHEJ1_HUMAN DNA repair protein involved in DNA nonhomologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination. May serve as a bridge between XRCC4 and the other NHEJ factors located at DNA ends, or may participate in reconfiguration of the end bound NHEJ factors to allow XRCC4 access to the DNA termini. It may act in concert with XRCC6/XRCC5 (Ku) to stimulate XRCC4-mediated joining of blunt ends and several types of mismatched ends that are noncomplementary or partially complementary.[6] [7] [8] Publication Abstract from PubMedNonhomologous end joining is a critical mechanism that repairs DNA double-strand breaks in human cells. In this work, we address the structural and functional role of the accessory protein PAXX [paralog of x-ray repair cross-complementing protein 4 (XRCC4) and XRCC4-like factor (XLF)] in this mechanism. Here, we report high-resolution cryo-electron microscopy (cryo-EM) and x-ray crystallography structures of the PAXX C-terminal Ku-binding motif bound to Ku70/80 and cryo-EM structures of PAXX bound to two alternate DNA-dependent protein kinase (DNA-PK) end-bridging dimers, mediated by either Ku80 or XLF. We identify residues critical for the Ku70/PAXX interaction in vitro and in cells. We demonstrate that PAXX and XLF can bind simultaneously to the Ku heterodimer and act as structural bridges in alternate forms of DNA-PK dimers. Last, we show that engagement of both proteins provides a complementary advantage for DNA end synapsis and end joining in cells. PAXX binding to the NHEJ machinery explains functional redundancy with XLF.,Seif-El-Dahan M, Kefala-Stavridi A, Frit P, Hardwick SW, Chirgadze DY, Maia De Oliviera T, Andreani J, Britton S, Barboule N, Bossaert M, Pandurangan AP, Meek K, Blundell TL, Ropars V, Calsou P, Charbonnier JB, Chaplin AK Sci Adv. 2023 Jun 2;9(22):eadg2834. doi: 10.1126/sciadv.adg2834. Epub 2023 May , 31. PMID:37256950[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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