3sr2
Crystal Structure of Human XLF-XRCC4 ComplexCrystal Structure of Human XLF-XRCC4 Complex
Structural highlights
Disease[NHEJ1_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] Function[XRCC4_HUMAN] Involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination. Binds to DNA and to DNA ligase IV (LIG4). The LIG4-XRCC4 complex is responsible for the NHEJ ligation step, and XRCC4 enhances the joining activity of LIG4. Binding of the LIG4-XRCC4 complex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends.[6] [7] [8] [9] [NHEJ1_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.[10] [11] [12] Publication Abstract from PubMedThe XLF-XRCC4 complex is essential for non-homologous end joining (NHEJ), the major repair pathway for DNA double-strand breaks (DSBs) in human cells. Yet, how XLF binds XRCC4 and impacts NHEJ functions has been enigmatic. Here, we report the XLF-XRCC4 complex crystal structure in combination with biophysical and mutational analyses to define XLF-XRCC4 interactions. Crystal and solution structures plus mutations characterize alternating XRCC4 and XLF head domain interfaces forming parallel super-helical filaments. XLF L115 Leu lock inserts into a hydrophobic pocket formed by XRCC4 M59, M61, K65, K99, F106, L108 in synergy with pseudo-symmetric beta-zipper hydrogen bonds to drive specificity. XLF C-terminus and DNA enhance parallel filament formation. Super-helical XLF-XRCC4 filaments form a positively charged channel to bind DNA and align ends for efficient ligation. Collective results reveal how human XLF and XRCC4 interact to bind DNA, suggest consequences of patient mutations, and support a unified molecular mechanism for XLF-XRCC4 stimulation of DNA ligation. XRCC4 interactions with XRCC4-like factor (XLF) create an extended grooved scaffold for DNA ligation and double-strand break repair.,Hammel M, Rey M, Yu Y, Mani RS, Classen S, Liu M, Pique ME, Fang S, Mahaney B, Weinfeld M, Schriemer DC, Lees-Miller SP, Tainer JA J Biol Chem. 2011 Jul 20. PMID:21775435[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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