| Structural highlights
Disease
[AIMP1_HUMAN] Defects in AIMP1 are the cause of leukodystrophy hypomyelinating type 3 (HLD3) [MIM:260600]. A severe autosomal recessive hypomyelinating leukodystrophy characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system.[1] [SYQ_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.
Function
[AIMP1_HUMAN] Non-catalytic component of the multisynthase complex. Stimulates the catalytic activity of cytoplasmic arginyl-tRNA synthase. Binds tRNA. Possesses inflammatory cytokine activity. Negatively regulates TGF-beta signaling through stabilization of SMURF2 by binding to SMURF2 and inhibiting its SMAD7-mediated degradation. Involved in glucose homeostasis through induction of glucagon secretion at low glucose levels. Promotes dermal fibroblast proliferation and wound repair. Regulates KDELR1-mediated retention of HSP90B1/gp96 in the endoplasmic reticulum. Plays a role in angiogenesis by inducing endothelial cell migration at low concentrations and endothelian cell apoptosis at high concentrations. Induces maturation of dendritic cells and monocyte cell adhesion. Modulates endothelial cell responses by degrading HIF-1A through interaction with PSMA7.[2] [3] [4] [5] [6] [7] [SYQ_HUMAN] Plays a critical role in brain development.[8] [SYRC_HUMAN] Forms part of a macromolecular complex that catalyzes the attachment of specific amino acids to cognate tRNAs during protein synthesis. Modulates the secretion of AIMP1 and may be involved in generation of the inflammatory cytokine EMAP2 from AIMP1.[9]
Publication Abstract from PubMed
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.
Structure of the ArgRS-GlnRS-AIMP1 complex and its implications for mammalian translation.,Fu Y, Kim Y, Jin KS, Kim HS, Kim JH, Wang D, Park M, Jo CH, Kwon NH, Kim D, Kim MH, Jeon YH, Hwang KY, Kim S, Cho Y Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15084-9. doi:, 10.1073/pnas.1408836111. Epub 2014 Oct 6. PMID:25288775[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Feinstein M, Markus B, Noyman I, Shalev H, Flusser H, Shelef I, Liani-Leibson K, Shorer Z, Cohen I, Khateeb S, Sivan S, Birk OS. Pelizaeus-Merzbacher-like disease caused by AIMP1/p43 homozygous mutation. Am J Hum Genet. 2010 Dec 10;87(6):820-8. doi: 10.1016/j.ajhg.2010.10.016. Epub, 2010 Nov 18. PMID:21092922 doi:10.1016/j.ajhg.2010.10.016
- ↑ Park SG, Jung KH, Lee JS, Jo YJ, Motegi H, Kim S, Shiba K. Precursor of pro-apoptotic cytokine modulates aminoacylation activity of tRNA synthetase. J Biol Chem. 1999 Jun 11;274(24):16673-6. PMID:10358004
- ↑ Shalak V, Kaminska M, Mitnacht-Kraus R, Vandenabeele P, Clauss M, Mirande M. The EMAPII cytokine is released from the mammalian multisynthetase complex after cleavage of its p43/proEMAPII component. J Biol Chem. 2001 Jun 29;276(26):23769-76. Epub 2001 Apr 16. PMID:11306575 doi:10.1074/jbc.M100489200
- ↑ Park SG, Kang YS, Ahn YH, Lee SH, Kim KR, Kim KW, Koh GY, Ko YG, Kim S. Dose-dependent biphasic activity of tRNA synthetase-associating factor, p43, in angiogenesis. J Biol Chem. 2002 Nov 22;277(47):45243-8. Epub 2002 Sep 16. PMID:12237313 doi:10.1074/jbc.M207934200
- ↑ Park H, Park SG, Lee JW, Kim T, Kim G, Ko YG, Kim S. Monocyte cell adhesion induced by a human aminoacyl-tRNA synthetase-associated factor, p43: identification of the related adhesion molecules and signal pathways. J Leukoc Biol. 2002 Feb;71(2):223-30. PMID:11818442
- ↑ Tandle AT, Calvani M, Uranchimeg B, Zahavi D, Melillo G, Libutti SK. Endothelial monocyte activating polypeptide-II modulates endothelial cell responses by degrading hypoxia-inducible factor-1alpha through interaction with PSMA7, a component of the proteasome. Exp Cell Res. 2009 Jul 1;315(11):1850-9. doi: 10.1016/j.yexcr.2009.03.021. Epub, 2009 Apr 10. PMID:19362550 doi:10.1016/j.yexcr.2009.03.021
- ↑ Renault L, Kerjan P, Pasqualato S, Menetrey J, Robinson JC, Kawaguchi S, Vassylyev DG, Yokoyama S, Mirande M, Cherfils J. Structure of the EMAPII domain of human aminoacyl-tRNA synthetase complex reveals evolutionary dimer mimicry. EMBO J. 2001 Feb 1;20(3):570-8. PMID:11157763 doi:10.1093/emboj/20.3.570
- ↑ Zhang X, Ling J, Barcia G, Jing L, Wu J, Barry BJ, Mochida GH, Hill RS, Weimer JM, Stein Q, Poduri A, Partlow JN, Ville D, Dulac O, Yu TW, Lam AT, Servattalab S, Rodriguez J, Boddaert N, Munnich A, Colleaux L, Zon LI, Soll D, Walsh CA, Nabbout R. Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. Am J Hum Genet. 2014 Apr 3;94(4):547-58. doi: 10.1016/j.ajhg.2014.03.003. Epub, 2014 Mar 20. PMID:24656866 doi:http://dx.doi.org/10.1016/j.ajhg.2014.03.003
- ↑ Bottoni A, Vignali C, Piccin D, Tagliati F, Luchin A, Zatelli MC, Uberti EC. Proteasomes and RARS modulate AIMP1/EMAP II secretion in human cancer cell lines. J Cell Physiol. 2007 Aug;212(2):293-7. PMID:17443684 doi:http://dx.doi.org/10.1002/jcp.21083
- ↑ Fu Y, Kim Y, Jin KS, Kim HS, Kim JH, Wang D, Park M, Jo CH, Kwon NH, Kim D, Kim MH, Jeon YH, Hwang KY, Kim S, Cho Y. Structure of the ArgRS-GlnRS-AIMP1 complex and its implications for mammalian translation. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15084-9. doi:, 10.1073/pnas.1408836111. Epub 2014 Oct 6. PMID:25288775 doi:http://dx.doi.org/10.1073/pnas.1408836111
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