Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5
Heart development in mammalian systems is controlled by combinatorial interactions of master cardiac transcription factors such as TBX5 and NKX2.5. They bind to promoters/enhancers of downstream targets as homo- or heteromultimeric complexes. They physically interact and synergistically regulate the...
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Veröffentlicht in: | Biochemistry (Easton) 2016-03, Vol.55 (12), p.1702-1710 |
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creator | Pradhan, Lagnajeet Gopal, Sunil Li, Shichang Ashur, Shayan Suryanarayanan, Saai Kasahara, Hideko Nam, Hyun-Joo |
description | Heart development in mammalian systems is controlled by combinatorial interactions of master cardiac transcription factors such as TBX5 and NKX2.5. They bind to promoters/enhancers of downstream targets as homo- or heteromultimeric complexes. They physically interact and synergistically regulate their target genes. To elucidate the molecular basis of the intermolecular interactions, a heterodimer and a homodimer of NKX2.5 and TBX5 were studied using X-ray crystallography. Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA and a crystal structure of TBX5 homodimer. The ternary complex structure of NKX2.5 and TBX5 with the target DNA shows physical interactions between the two proteins through Lys158 (NKX2.5), Asp140 (TBX5), and Pro142 (TBX5), residues that are highly conserved in TBX and NKX families across species. Extensive homodimeric interactions were observed between the TBX5 proteins in both crystal structures. In particular, in the crystal structure of TBX5 protein that includes the N-terminal and DNA binding domains, intermolecular interactions were mediated by the N-terminal domain of the protein. The N-terminal domain of TBX5 was predicted to be “intrinsically unstructured”, and in one of the two molecules in an asymmetric unit, the N-terminal domain assumes a β-strand conformation bridging two β-sheets from the two molecules. The structures reported here may represent general mechanisms for combinatorial interactions among transcription factors regulating developmental processes. |
doi_str_mv | 10.1021/acs.biochem.6b00171 |
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They bind to promoters/enhancers of downstream targets as homo- or heteromultimeric complexes. They physically interact and synergistically regulate their target genes. To elucidate the molecular basis of the intermolecular interactions, a heterodimer and a homodimer of NKX2.5 and TBX5 were studied using X-ray crystallography. Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA and a crystal structure of TBX5 homodimer. The ternary complex structure of NKX2.5 and TBX5 with the target DNA shows physical interactions between the two proteins through Lys158 (NKX2.5), Asp140 (TBX5), and Pro142 (TBX5), residues that are highly conserved in TBX and NKX families across species. Extensive homodimeric interactions were observed between the TBX5 proteins in both crystal structures. In particular, in the crystal structure of TBX5 protein that includes the N-terminal and DNA binding domains, intermolecular interactions were mediated by the N-terminal domain of the protein. The N-terminal domain of TBX5 was predicted to be “intrinsically unstructured”, and in one of the two molecules in an asymmetric unit, the N-terminal domain assumes a β-strand conformation bridging two β-sheets from the two molecules. The structures reported here may represent general mechanisms for combinatorial interactions among transcription factors regulating developmental processes.</description><identifier>ISSN: 0006-2960</identifier><identifier>EISSN: 1520-4995</identifier><identifier>DOI: 10.1021/acs.biochem.6b00171</identifier><identifier>PMID: 26926761</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amino Acid Sequence ; Crystallography, X-Ray ; Heart ; Homeobox Protein Nkx-2.5 ; Homeodomain Proteins - chemistry ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; Humans ; Molecular Sequence Data ; Protein Binding - physiology ; Protein Structure, Secondary ; Protein Structure, Tertiary ; T-Box Domain Proteins - chemistry ; T-Box Domain Proteins - genetics ; T-Box Domain Proteins - metabolism ; Transcription Factors - chemistry ; Transcription Factors - genetics ; Transcription Factors - metabolism</subject><ispartof>Biochemistry (Easton), 2016-03, Vol.55 (12), p.1702-1710</ispartof><rights>Copyright © 2016 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a411t-8bf53bf49c3406ba7749acfc005c56704bd84016b9c3c896aee302b99d908ad03</citedby><cites>FETCH-LOGICAL-a411t-8bf53bf49c3406ba7749acfc005c56704bd84016b9c3c896aee302b99d908ad03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.biochem.6b00171$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.biochem.6b00171$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26926761$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pradhan, Lagnajeet</creatorcontrib><creatorcontrib>Gopal, Sunil</creatorcontrib><creatorcontrib>Li, Shichang</creatorcontrib><creatorcontrib>Ashur, Shayan</creatorcontrib><creatorcontrib>Suryanarayanan, Saai</creatorcontrib><creatorcontrib>Kasahara, Hideko</creatorcontrib><creatorcontrib>Nam, Hyun-Joo</creatorcontrib><title>Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5</title><title>Biochemistry (Easton)</title><addtitle>Biochemistry</addtitle><description>Heart development in mammalian systems is controlled by combinatorial interactions of master cardiac transcription factors such as TBX5 and NKX2.5. They bind to promoters/enhancers of downstream targets as homo- or heteromultimeric complexes. They physically interact and synergistically regulate their target genes. To elucidate the molecular basis of the intermolecular interactions, a heterodimer and a homodimer of NKX2.5 and TBX5 were studied using X-ray crystallography. Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA and a crystal structure of TBX5 homodimer. The ternary complex structure of NKX2.5 and TBX5 with the target DNA shows physical interactions between the two proteins through Lys158 (NKX2.5), Asp140 (TBX5), and Pro142 (TBX5), residues that are highly conserved in TBX and NKX families across species. Extensive homodimeric interactions were observed between the TBX5 proteins in both crystal structures. In particular, in the crystal structure of TBX5 protein that includes the N-terminal and DNA binding domains, intermolecular interactions were mediated by the N-terminal domain of the protein. The N-terminal domain of TBX5 was predicted to be “intrinsically unstructured”, and in one of the two molecules in an asymmetric unit, the N-terminal domain assumes a β-strand conformation bridging two β-sheets from the two molecules. The structures reported here may represent general mechanisms for combinatorial interactions among transcription factors regulating developmental processes.</description><subject>Amino Acid Sequence</subject><subject>Crystallography, X-Ray</subject><subject>Heart</subject><subject>Homeobox Protein Nkx-2.5</subject><subject>Homeodomain Proteins - chemistry</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Molecular Sequence Data</subject><subject>Protein Binding - physiology</subject><subject>Protein Structure, Secondary</subject><subject>Protein Structure, Tertiary</subject><subject>T-Box Domain Proteins - chemistry</subject><subject>T-Box Domain Proteins - genetics</subject><subject>T-Box Domain Proteins - metabolism</subject><subject>Transcription Factors - chemistry</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEFLwzAUx4Mobk4_gSA5emn30qZJc9ThVBx6mbBbSNIUO9pmJuvBb2_mqkfhweOR3_898kPomkBKICNzZUKqG2c-bJcyDUA4OUFTUmSQUCGKUzQFAJZkgsEEXYSwjSMFTs_RJGMiY5yRKVo993vrO9daM7TK459RmX3j-oBdjRfKV40yeO1VH4xvdocXvIyE8wG_vmyytMCqr_D6flNcorNatcFejX2G3pcP68VTsnp7fF7crRJFCdknpa6LXNdUmJwC04pzKpSpDUBhCsaB6qqkQJiOgCkFU9bmkGkhKgGlqiCfodvj3p13n4MNe9k1wdi2Vb11Q5CEcw6xWB7R_Iga70LwtpY733TKf0kC8qBRRo1y1ChHjTF1Mx4YdGerv8yvtwjMj8AhvXWD7-N__135DTuzf78</recordid><startdate>20160329</startdate><enddate>20160329</enddate><creator>Pradhan, Lagnajeet</creator><creator>Gopal, Sunil</creator><creator>Li, Shichang</creator><creator>Ashur, Shayan</creator><creator>Suryanarayanan, Saai</creator><creator>Kasahara, Hideko</creator><creator>Nam, Hyun-Joo</creator><general>American Chemical Society</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></search><sort><creationdate>20160329</creationdate><title>Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5</title><author>Pradhan, Lagnajeet ; Gopal, Sunil ; Li, Shichang ; Ashur, Shayan ; Suryanarayanan, Saai ; Kasahara, Hideko ; Nam, Hyun-Joo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a411t-8bf53bf49c3406ba7749acfc005c56704bd84016b9c3c896aee302b99d908ad03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Amino Acid Sequence</topic><topic>Crystallography, X-Ray</topic><topic>Heart</topic><topic>Homeobox Protein Nkx-2.5</topic><topic>Homeodomain Proteins - chemistry</topic><topic>Homeodomain Proteins - genetics</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Humans</topic><topic>Molecular Sequence Data</topic><topic>Protein Binding - physiology</topic><topic>Protein Structure, Secondary</topic><topic>Protein Structure, Tertiary</topic><topic>T-Box Domain Proteins - chemistry</topic><topic>T-Box Domain Proteins - genetics</topic><topic>T-Box Domain Proteins - metabolism</topic><topic>Transcription Factors - chemistry</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pradhan, Lagnajeet</creatorcontrib><creatorcontrib>Gopal, Sunil</creatorcontrib><creatorcontrib>Li, Shichang</creatorcontrib><creatorcontrib>Ashur, Shayan</creatorcontrib><creatorcontrib>Suryanarayanan, Saai</creatorcontrib><creatorcontrib>Kasahara, Hideko</creatorcontrib><creatorcontrib>Nam, Hyun-Joo</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>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pradhan, Lagnajeet</au><au>Gopal, Sunil</au><au>Li, Shichang</au><au>Ashur, Shayan</au><au>Suryanarayanan, Saai</au><au>Kasahara, Hideko</au><au>Nam, Hyun-Joo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2016-03-29</date><risdate>2016</risdate><volume>55</volume><issue>12</issue><spage>1702</spage><epage>1710</epage><pages>1702-1710</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><abstract>Heart development in mammalian systems is controlled by combinatorial interactions of master cardiac transcription factors such as TBX5 and NKX2.5. They bind to promoters/enhancers of downstream targets as homo- or heteromultimeric complexes. They physically interact and synergistically regulate their target genes. To elucidate the molecular basis of the intermolecular interactions, a heterodimer and a homodimer of NKX2.5 and TBX5 were studied using X-ray crystallography. Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA and a crystal structure of TBX5 homodimer. The ternary complex structure of NKX2.5 and TBX5 with the target DNA shows physical interactions between the two proteins through Lys158 (NKX2.5), Asp140 (TBX5), and Pro142 (TBX5), residues that are highly conserved in TBX and NKX families across species. Extensive homodimeric interactions were observed between the TBX5 proteins in both crystal structures. In particular, in the crystal structure of TBX5 protein that includes the N-terminal and DNA binding domains, intermolecular interactions were mediated by the N-terminal domain of the protein. The N-terminal domain of TBX5 was predicted to be “intrinsically unstructured”, and in one of the two molecules in an asymmetric unit, the N-terminal domain assumes a β-strand conformation bridging two β-sheets from the two molecules. The structures reported here may represent general mechanisms for combinatorial interactions among transcription factors regulating developmental processes.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>26926761</pmid><doi>10.1021/acs.biochem.6b00171</doi><tpages>9</tpages></addata></record> |
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subjects | Amino Acid Sequence Crystallography, X-Ray Heart Homeobox Protein Nkx-2.5 Homeodomain Proteins - chemistry Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humans Molecular Sequence Data Protein Binding - physiology Protein Structure, Secondary Protein Structure, Tertiary T-Box Domain Proteins - chemistry T-Box Domain Proteins - genetics T-Box Domain Proteins - metabolism Transcription Factors - chemistry Transcription Factors - genetics Transcription Factors - metabolism |
title | Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5 |
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