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Gwon, Gwang Hyeon,Kim, Youngran,Liu, Yaqi,Watson, Adam T.,Jo, Aera,Etheridge, Thomas J.,Yuan, Fenghua,Zhang, Yanbin,Kim, YoungChang,Carr, Anthony M.,Cho, Yunje Cold Spring Harbor Laboratory Press 2014 Genes & development Vol.28 No.20
<P>Fanconi anemia (FA) is an autosomal recessive genetic disorder caused by defects in FA genes responsible for processing DNA interstrand cross-links (ICLs). FA-associated nuclease (FAN1) is recruited to lesions by a monoubiquitinated FANCI–FANCD2 (ID) complex and participates in ICL repair. Here, Gwon et al. determined the crystal structure of <I>Pseudomonas aeruginosa</I> FAN1 (<I>Pa</I>FAN1) lacking the UBZ (ubiquitin-binding zinc) domain in complex with 5′ flap DNA. The <I>Pa</I>FAN1 structure provides insights into how FAN1 integrates with the FA complex to participate in ICL repair.</P><P>Fanconi anemia (FA) is an autosomal recessive genetic disorder caused by defects in any of 15 FA genes responsible for processing DNA interstrand cross-links (ICLs). The ultimate outcome of the FA pathway is resolution of cross-links, which requires structure-selective nucleases. FA-associated nuclease 1 (FAN1) is believed to be recruited to lesions by a monoubiquitinated FANCI–FANCD2 (ID) complex and participates in ICL repair. Here, we determined the crystal structure of <I>Pseudomonas aeruginosa</I> FAN1 (<I>Pa</I>FAN1) lacking the UBZ (ubiquitin-binding zinc) domain in complex with 5′ flap DNA. All four domains of the right-hand-shaped <I>Pa</I>FAN1 are involved in DNA recognition, with each domain playing a specific role in bending DNA at the nick. The six-helix bundle that binds the junction connects to the catalytic viral replication and repair (VRR) nuclease (VRR nuc) domain, enabling FAN1 to incise the scissile phosphate a few bases distant from the junction. The six-helix bundle also inhibits the cleavage of intact Holliday junctions. <I>Pa</I>FAN1 shares several conserved features with other flap structure-selective nucleases despite structural differences. A clamping motion of the domains around the wedge helix, which acts as a pivot, facilitates nucleolytic cleavage. The <I>Pa</I>FAN1 structure provides insights into how archaeal Holliday junction resolvases evolved to incise 5′ flap substrates and how FAN1 integrates with the FA complex to participate in ICL repair.</P>
Structure of the ArgRS–GlnRS–AIMP1 complex and its implications for mammalian translation
Fu, Yaoyao,Kim, Youngran,Jin, Kyeong Sik,Kim, Hyun Sook,Kim, Jong Hyun,Wang, DongMing,Park, Minyoung,Jo, Chang Hwa,Kwon, Nam Hoon,Kim, Doyeun,Kim, Myung Hee,Jeon, Young Ho,Hwang, Kwang Yeon,Kim, Sungh National Academy of Sciences 2014 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.111 No.42
<P><B>Significance</B></P><P>In higher eukaryotes, aminoacyl-tRNA synthetases (ARSs) are assembled to form a multisynthetase complex (MSC), which plays critical roles in translation and nontranslation functions essential for cell growth and survival of organisms. The MSC complex is comprised of nine different ARSs and three accessary proteins. The crystal structure of the arginyl-tRNA synthetase (ArgRS)–glutaminyl-tRNA synthase–aminoacyl tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1) subcomplex reveals that the N-terminal domains of ArgRS and AIMP1 form an extended coiled-coil structure, which provides a central depot for the assembly of a ternary complex. The stability of the N-terminal helix of ArgRS is critical for its ARS activity and noncanonical function of the subcomplex, explaining the significance of the MSC structure in translation and cellular functions.</P><P>In higher eukaryotes, one of the two arginyl-tRNA synthetases (ArgRSs) has evolved to have an extended N-terminal domain that plays a crucial role in protein synthesis and cell growth and in integration into the multisynthetase complex (MSC). Here, we report a crystal structure of the MSC subcomplex comprising ArgRS, glutaminyl-tRNA synthetase (GlnRS), and the auxiliary factor aminoacyl tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1)/p43. In this complex, the N-terminal domain of ArgRS forms a long coiled-coil structure with the N-terminal helix of AIMP1 and anchors the C-terminal core of GlnRS, thereby playing a central role in assembly of the three components. Mutation of AIMP1 destabilized the N-terminal helix of ArgRS and abrogated its catalytic activity. Mutation of the N-terminal helix of ArgRS liberated GlnRS, which is known to control cell death. This ternary complex was further anchored to AIMP2/p38 through interaction with AIMP1. These findings demonstrate the importance of interactions between the N-terminal domains of ArgRS and AIMP1 for the catalytic and noncatalytic activities of ArgRS and for the assembly of the higher-order MSC protein complex.</P>