3w03
XLF-XRCC4 complexXLF-XRCC4 complex
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 PubMedXRCC4 (X-ray cross-complementation group 4) and XLF (XRCC4-like factor) are two essential interacting proteins in the human NHEJ (non-homologous end-joining) pathway that repairs DNA DSBs (double-strand breaks). The individual crystal structures show that the dimeric proteins are homologues with protomers containing head domains and helical coiled-coil tails related by approximate two-fold symmetry. Biochemical, mutagenesis, biophysical and structural studies have identified the regions of interaction between the two proteins and suggested models for the XLF-XRCC4 complex. An 8.5 A (1 A = 0.1 nm) resolution crystal structure of XLF-XRCC4 solved by molecular replacement, together with gel filtration and nano-ESI (nano-electrospray ionization)-MS results, demonstrates that XLF and XRCC4 dimers interact through their head domains and form an alternating left-handed helical structure with polypeptide coiled coils and pseudo-dyads of individual XLF and XRCC4 dimers at right angles to the helical axis. Non-homologous end-joining partners in a helical dance: structural studies of XLF-XRCC4 interactions.,Wu Q, Ochi T, Matak-Vinkovic D, Robinson CV, Chirgadze DY, Blundell TL Biochem Soc Trans. 2011 Oct;39(5):1387-92, suppl 2 p following 1392. PMID:21936820[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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