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5w6m

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Crystal structure of the human histidyl-tRNA synthetase mutant D175E

Structural highlights

5w6m is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.696Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

HARS1_HUMAN Usher syndrome type 3;Autosomal dominant Charcot-Marie-Tooth disease type 2W. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.

Function

HARS1_HUMAN Catalyzes the ATP-dependent ligation of histidine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP) (PubMed:29235198). Plays a role in axon guidance (PubMed:26072516).^[1] ^[2]

Publication Abstract from PubMed

Aminoacyl-transfer RNA (tRNA) synthetases (aaRSs) are the largest protein family causatively linked to neurodegenerative Charcot-Marie-Tooth (CMT) disease. Dominant mutations cause the disease, and studies of CMT disease-causing mutant glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase (TyrRS) showed their mutations create neomorphic structures consistent with a gain-of-function mechanism. In contrast, based on a haploid yeast model, loss of aminoacylation function was reported for CMT disease mutants in histidyl-tRNA synthetase (HisRS). However, neither that nor prior work of any CMT disease-causing aaRS investigated the aminoacylation status of tRNAs in the cellular milieu of actual patients. Using an assay that interrogated aminoacylation levels in patient cells, we investigated a HisRS-linked CMT disease family with the most severe disease phenotype. Strikingly, no difference in charged tRNA levels between normal and diseased family members was found. In confirmation, recombinant versions of 4 other HisRS CMT disease-causing mutants showed no correlation between activity loss in vitro and severity of phenotype in vivo. Indeed, a mutation having the most detrimental impact on activity was associated with a mild disease phenotype. In further work, using 3 independent biophysical analyses, structural opening (relaxation) of mutant HisRSs at the dimer interface best correlated with disease severity. In fact, the HisRS mutation in the severely afflicted patient family caused the largest degree of structural relaxation. These data suggest that HisRS-linked CMT disease arises from open conformation-induced mechanisms distinct from loss of aminoacylation.

CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells.,Blocquel D, Sun L, Matuszek Z, Li S, Weber T, Kuhle B, Kooi G, Wei N, Baets J, Pan T, Schimmel P, Yang XL Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19440-19448. doi:, 10.1073/pnas.1908288116. Epub 2019 Sep 9. PMID:31501329^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Safka Brozkova D, Deconinck T, Griffin LB, Ferbert A, Haberlova J, Mazanec R, Lassuthova P, Roth C, Pilunthanakul T, Rautenstrauss B, Janecke AR, Zavadakova P, Chrast R, Rivolta C, Zuchner S, Antonellis A, Beg AA, De Jonghe P, Senderek J, Seeman P, Baets J. Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies. Brain. 2015 Aug;138(Pt 8):2161-72. doi: 10.1093/brain/awv158. Epub 2015 Jun 13. PMID:26072516 doi:http://dx.doi.org/10.1093/brain/awv158
↑ Abbott JA, Meyer-Schuman R, Lupo V, Feely S, Mademan I, Oprescu SN, Griffin LB, Alberti MA, Casasnovas C, Aharoni S, Basel-Vanagaite L, Zuchner S, De Jonghe P, Baets J, Shy ME, Espinos C, Demeler B, Antonellis A, Francklyn C. Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy. Hum Mutat. 2018 Mar;39(3):415-432. doi: 10.1002/humu.23380. Epub 2017 Dec 26. PMID:29235198 doi:http://dx.doi.org/10.1002/humu.23380
↑ Blocquel D, Sun L, Matuszek Z, Li S, Weber T, Kuhle B, Kooi G, Wei N, Baets J, Pan T, Schimmel P, Yang XL. CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells. Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19440-19448. doi:, 10.1073/pnas.1908288116. Epub 2019 Sep 9. PMID:31501329 doi:http://dx.doi.org/10.1073/pnas.1908288116

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5w6m"

Categories: Homo sapiens | Large Structures | Blocquel D | Yang XL

@@ Line 3: / Line 3: @@
 <StructureSection load='5w6m' size='340' side='right'caption='[[5w6m]], [[Resolution|resolution]] 3.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5w6m]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W6M OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5W6M FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5w6m]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W6M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5W6M FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HARS, HRS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.696&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histidine--tRNA_ligase Histidine--tRNA ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.1.1.21 6.1.1.21] </span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5w6m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w6m OCA], [https://pdbe.org/5w6m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5w6m RCSB], [https://www.ebi.ac.uk/pdbsum/5w6m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5w6m ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5w6m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w6m OCA], [http://pdbe.org/5w6m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w6m RCSB], [http://www.ebi.ac.uk/pdbsum/5w6m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w6m ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/SYHC_HUMAN SYHC_HUMAN]] Defects in HARS are a cause of Usher syndrome type 3B (USH3B) [MIM:[http://omim.org/entry/614504 614504]]. USH3B is a syndrome characterized by progressive vision and hearing loss during early childhood. Some patients have the so-called 'Charles Bonnet syndrome,' involving decreased visual acuity and vivid visual hallucinations. USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH3 is characterized by postlingual, progressive hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa symptoms, including nyctalopia, constriction of the visual fields, and loss of central visual acuity, usually by the second decade of life.<ref>PMID:22279524</ref>   Note=HARS mutations may be involved in peripheral neuropathy, a disease mainly characterized by distal motor and sensory dysfunction. Inherited peripheral neuropathies are clinically and genetically heterogeneous with variable age of onset and reduced penetrance associated with specific loci. HARS mutations may directly predispose patients to peripheral neuropathy or may modify a peripheral neuropathy phenotype by contributing to the genetic and environmental load in a given patient (PubMed:22930593).
+[https://www.uniprot.org/uniprot/HARS1_HUMAN HARS1_HUMAN] Usher syndrome type 3;Autosomal dominant Charcot-Marie-Tooth disease type 2W. The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/HARS1_HUMAN HARS1_HUMAN] Catalyzes the ATP-dependent ligation of histidine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP) (PubMed:29235198). Plays a role in axon guidance (PubMed:26072516).<ref>PMID:26072516</ref> <ref>PMID:29235198</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 27: @@
 __TOC__
 </StructureSection>
-[[Category: Histidine--tRNA ligase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Blocquel, D]]
+[[Category: Blocquel D]]
-[[Category: Yang, X L]]
+[[Category: Yang XL]]
-[[Category: Cmt mutant]]
-[[Category: Ligase]]
-[[Category: Trna-synthetase]]

5w6m

From Proteopedia

Current revision

Crystal structure of the human histidyl-tRNA synthetase mutant D175E

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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