Biophysical characterization Of Alpers encephalopathy associated mutants of human mitochondrial phenylalanyl‐tRNA synthetase
Mutations in nucleus‐encoded mitochondrial aminoacyl‐tRNA synthetases (mitaaRSs) lead to defects in mitochondrial translation affecting the expression and function of 13 subunits of the respiratory chain complex leading to diverse pathological conditions. Mutations in the FARS2 gene encoding human m...
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| description | Mutations in nucleus‐encoded mitochondrial aminoacyl‐tRNA synthetases (mitaaRSs) lead to defects in mitochondrial translation affecting the expression and function of 13 subunits of the respiratory chain complex leading to diverse pathological conditions. Mutations in the FARS2 gene encoding human mitochondrial phenylalanyl‐tRNA synthetase (HsmitPheRS) have been found to be associated with two different clinical representations, infantile Alpers encephalopathy and spastic paraplegia. Here we have studied three pathogenic mutants (Tyr144Cys, Ile329Thr, and Asp391Val) associated with Alpers encephalopathy to understand how these variants affect the biophysical properties of the enzyme. These mutants have already been reported to have reduced aminoacylation activity. Our study established that the mutants are significantly more thermolabile compared to the wild‐type enzyme with reduced solubility in vitro. The presence of aggregation‐prone insoluble HsmitPheRS variants could have a detrimental impact on organellar translation, and potentially impact normal mitochondrial function. © 2019 IUBMB Life, 71(8): 1141–1149, 2019 © 2019 IUBMB Life, 71(8):1141–1149, 2019 |
| doi_str_mv | 10.1002/iub.2114 |
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Mutations in the FARS2 gene encoding human mitochondrial phenylalanyl‐tRNA synthetase (HsmitPheRS) have been found to be associated with two different clinical representations, infantile Alpers encephalopathy and spastic paraplegia. Here we have studied three pathogenic mutants (Tyr144Cys, Ile329Thr, and Asp391Val) associated with Alpers encephalopathy to understand how these variants affect the biophysical properties of the enzyme. These mutants have already been reported to have reduced aminoacylation activity. Our study established that the mutants are significantly more thermolabile compared to the wild‐type enzyme with reduced solubility in vitro. The presence of aggregation‐prone insoluble HsmitPheRS variants could have a detrimental impact on organellar translation, and potentially impact normal mitochondrial function. © 2019 IUBMB Life, 71(8): 1141–1149, 2019 © 2019 IUBMB Life, 71(8):1141–1149, 2019</description><identifier>ISSN: 1521-6543</identifier><identifier>EISSN: 1521-6551</identifier><identifier>DOI: 10.1002/iub.2114</identifier><identifier>PMID: 31241862</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>Adenosine Triphosphate - chemistry ; Aminoacylation ; Diffuse Cerebral Sclerosis of Schilder - enzymology ; Diffuse Cerebral Sclerosis of Schilder - genetics ; Electron transport ; Encephalopathy ; Enzymes ; Escherichia coli - metabolism ; Genome, Bacterial ; HsmitPheRS ; Humans ; Hydrogen-Ion Concentration ; infantile Alpers encephalopathy ; Ligands ; Light ; mitaaRSs ; Mitochondria ; Mitochondria - enzymology ; Mitochondrial Proteins - genetics ; Mitochondrial Proteins - physiology ; Mutation ; Paraplegia - enzymology ; Paraplegia - genetics ; Particle Size ; Phenylalanine - chemistry ; Phenylalanine-tRNA Ligase - genetics ; Phenylalanine-tRNA Ligase - physiology ; Plasmids - metabolism ; Protein Biosynthesis ; Solubility ; Spastic paraplegia ; Temperature ; Translation ; tRNA</subject><ispartof>IUBMB life, 2019-08, Vol.71 (8), p.1141-1149</ispartof><rights>2019 International Union of Biochemistry and Molecular Biology</rights><rights>2019 International Union of Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3834-4a83a8e0dc44eab722bd941cc3274cb0254888c77bdd710d1135c5e9f9bc271a3</citedby><cites>FETCH-LOGICAL-c3834-4a83a8e0dc44eab722bd941cc3274cb0254888c77bdd710d1135c5e9f9bc271a3</cites><orcidid>0000-0002-1451-7524 ; 0000-0003-2970-4901 ; 0000-0002-5318-1605</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fiub.2114$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fiub.2114$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,781,785,1418,1434,27926,27927,45576,45577,46411,46835</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31241862$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chakraborty, Shruti</creatorcontrib><creatorcontrib>Ibba, Michael</creatorcontrib><creatorcontrib>Banerjee, Rajat</creatorcontrib><title>Biophysical characterization Of Alpers encephalopathy associated mutants of human mitochondrial phenylalanyl‐tRNA synthetase</title><title>IUBMB life</title><addtitle>IUBMB Life</addtitle><description>Mutations in nucleus‐encoded mitochondrial aminoacyl‐tRNA synthetases (mitaaRSs) lead to defects in mitochondrial translation affecting the expression and function of 13 subunits of the respiratory chain complex leading to diverse pathological conditions. Mutations in the FARS2 gene encoding human mitochondrial phenylalanyl‐tRNA synthetase (HsmitPheRS) have been found to be associated with two different clinical representations, infantile Alpers encephalopathy and spastic paraplegia. Here we have studied three pathogenic mutants (Tyr144Cys, Ile329Thr, and Asp391Val) associated with Alpers encephalopathy to understand how these variants affect the biophysical properties of the enzyme. These mutants have already been reported to have reduced aminoacylation activity. Our study established that the mutants are significantly more thermolabile compared to the wild‐type enzyme with reduced solubility in vitro. The presence of aggregation‐prone insoluble HsmitPheRS variants could have a detrimental impact on organellar translation, and potentially impact normal mitochondrial function. © 2019 IUBMB Life, 71(8): 1141–1149, 2019 © 2019 IUBMB Life, 71(8):1141–1149, 2019</description><subject>Adenosine Triphosphate - chemistry</subject><subject>Aminoacylation</subject><subject>Diffuse Cerebral Sclerosis of Schilder - enzymology</subject><subject>Diffuse Cerebral Sclerosis of Schilder - genetics</subject><subject>Electron transport</subject><subject>Encephalopathy</subject><subject>Enzymes</subject><subject>Escherichia coli - metabolism</subject><subject>Genome, Bacterial</subject><subject>HsmitPheRS</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>infantile Alpers encephalopathy</subject><subject>Ligands</subject><subject>Light</subject><subject>mitaaRSs</subject><subject>Mitochondria</subject><subject>Mitochondria - enzymology</subject><subject>Mitochondrial Proteins - genetics</subject><subject>Mitochondrial Proteins - physiology</subject><subject>Mutation</subject><subject>Paraplegia - enzymology</subject><subject>Paraplegia - genetics</subject><subject>Particle Size</subject><subject>Phenylalanine - chemistry</subject><subject>Phenylalanine-tRNA Ligase - genetics</subject><subject>Phenylalanine-tRNA Ligase - physiology</subject><subject>Plasmids - metabolism</subject><subject>Protein Biosynthesis</subject><subject>Solubility</subject><subject>Spastic paraplegia</subject><subject>Temperature</subject><subject>Translation</subject><subject>tRNA</subject><issn>1521-6543</issn><issn>1521-6551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1K3kAUhodSqdYWvAIZ6MZNdP7yZbL8_LBVEAXRdTiZnJCRJJPOTJC4EC-h19gr6fhTCwXP4pyzeHh44SVkj7NDzpg4snN9KDhXH8gOzwXPVnnOP779Sm6TzyHcsjQFKz-RbcmF4noldsjDsXVTtwRroKemAw8morf3EK0b6WVL1_2EPlAcDU4d9G6C2C0UQnDGQsSGDnOEMQbqWtrNA4x0sNGZzo2Nt8k5dTguPfSQ9u_HX_HqYk3DMsYOIwT8QrZa6AN-fb275Ob7yfXmNDu__HG2WZ9nRmqpMgVagkbWGKUQ6kKIuikVN0aKQpmaiVxprU1R1E1TcNZwLnOTY9mWtREFB7lLDl68k3c_ZwyxGmww2KdY6OZQCbHiYsWElAn99h9662Y_pnSJystSaKnLf0LjXQge22rydgC_VJxVT51UqZPqqZOE7r8K53rA5g38W0ICshfgzva4vCuqzm6On4V_ABqdmHg</recordid><startdate>201908</startdate><enddate>201908</enddate><creator>Chakraborty, Shruti</creator><creator>Ibba, Michael</creator><creator>Banerjee, Rajat</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-1451-7524</orcidid><orcidid>https://orcid.org/0000-0003-2970-4901</orcidid><orcidid>https://orcid.org/0000-0002-5318-1605</orcidid></search><sort><creationdate>201908</creationdate><title>Biophysical characterization Of Alpers encephalopathy associated mutants of human mitochondrial phenylalanyl‐tRNA synthetase</title><author>Chakraborty, Shruti ; Ibba, Michael ; Banerjee, Rajat</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3834-4a83a8e0dc44eab722bd941cc3274cb0254888c77bdd710d1135c5e9f9bc271a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adenosine Triphosphate - chemistry</topic><topic>Aminoacylation</topic><topic>Diffuse Cerebral Sclerosis of Schilder - enzymology</topic><topic>Diffuse Cerebral Sclerosis of Schilder - genetics</topic><topic>Electron transport</topic><topic>Encephalopathy</topic><topic>Enzymes</topic><topic>Escherichia coli - metabolism</topic><topic>Genome, Bacterial</topic><topic>HsmitPheRS</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>infantile Alpers encephalopathy</topic><topic>Ligands</topic><topic>Light</topic><topic>mitaaRSs</topic><topic>Mitochondria</topic><topic>Mitochondria - enzymology</topic><topic>Mitochondrial Proteins - genetics</topic><topic>Mitochondrial Proteins - physiology</topic><topic>Mutation</topic><topic>Paraplegia - enzymology</topic><topic>Paraplegia - genetics</topic><topic>Particle Size</topic><topic>Phenylalanine - chemistry</topic><topic>Phenylalanine-tRNA Ligase - genetics</topic><topic>Phenylalanine-tRNA Ligase - physiology</topic><topic>Plasmids - metabolism</topic><topic>Protein Biosynthesis</topic><topic>Solubility</topic><topic>Spastic paraplegia</topic><topic>Temperature</topic><topic>Translation</topic><topic>tRNA</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chakraborty, Shruti</creatorcontrib><creatorcontrib>Ibba, Michael</creatorcontrib><creatorcontrib>Banerjee, Rajat</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>IUBMB life</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chakraborty, Shruti</au><au>Ibba, Michael</au><au>Banerjee, Rajat</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Biophysical characterization Of Alpers encephalopathy associated mutants of human mitochondrial phenylalanyl‐tRNA synthetase</atitle><jtitle>IUBMB life</jtitle><addtitle>IUBMB Life</addtitle><date>2019-08</date><risdate>2019</risdate><volume>71</volume><issue>8</issue><spage>1141</spage><epage>1149</epage><pages>1141-1149</pages><issn>1521-6543</issn><eissn>1521-6551</eissn><abstract>Mutations in nucleus‐encoded mitochondrial aminoacyl‐tRNA synthetases (mitaaRSs) lead to defects in mitochondrial translation affecting the expression and function of 13 subunits of the respiratory chain complex leading to diverse pathological conditions. Mutations in the FARS2 gene encoding human mitochondrial phenylalanyl‐tRNA synthetase (HsmitPheRS) have been found to be associated with two different clinical representations, infantile Alpers encephalopathy and spastic paraplegia. Here we have studied three pathogenic mutants (Tyr144Cys, Ile329Thr, and Asp391Val) associated with Alpers encephalopathy to understand how these variants affect the biophysical properties of the enzyme. These mutants have already been reported to have reduced aminoacylation activity. Our study established that the mutants are significantly more thermolabile compared to the wild‐type enzyme with reduced solubility in vitro. The presence of aggregation‐prone insoluble HsmitPheRS variants could have a detrimental impact on organellar translation, and potentially impact normal mitochondrial function. © 2019 IUBMB Life, 71(8): 1141–1149, 2019 © 2019 IUBMB Life, 71(8):1141–1149, 2019</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>31241862</pmid><doi>10.1002/iub.2114</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-1451-7524</orcidid><orcidid>https://orcid.org/0000-0003-2970-4901</orcidid><orcidid>https://orcid.org/0000-0002-5318-1605</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adenosine Triphosphate - chemistry Aminoacylation Diffuse Cerebral Sclerosis of Schilder - enzymology Diffuse Cerebral Sclerosis of Schilder - genetics Electron transport Encephalopathy Enzymes Escherichia coli - metabolism Genome, Bacterial HsmitPheRS Humans Hydrogen-Ion Concentration infantile Alpers encephalopathy Ligands Light mitaaRSs Mitochondria Mitochondria - enzymology Mitochondrial Proteins - genetics Mitochondrial Proteins - physiology Mutation Paraplegia - enzymology Paraplegia - genetics Particle Size Phenylalanine - chemistry Phenylalanine-tRNA Ligase - genetics Phenylalanine-tRNA Ligase - physiology Plasmids - metabolism Protein Biosynthesis Solubility Spastic paraplegia Temperature Translation tRNA |
| title | Biophysical characterization Of Alpers encephalopathy associated mutants of human mitochondrial phenylalanyl‐tRNA synthetase |
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