The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms
Forkhead-associated (FHA) domains are a class of ubiquitous signaling modules that appear to function through interactions with phosphorylated target molecules. We have used oriented peptide library screening to determine the optimal phosphopeptide binding motifs recognized by several FHA domains, i...
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| Veröffentlicht in: | Molecular cell 2000-11, Vol.6 (5), p.1169-1182 |
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| creator | Durocher, D Taylor, I A Sarbassova, D Haire, L F Westcott, S L Jackson, S P Smerdon, S J Yaffe, M B |
| description | Forkhead-associated (FHA) domains are a class of ubiquitous signaling modules that appear to function through interactions with phosphorylated target molecules. We have used oriented peptide library screening to determine the optimal phosphopeptide binding motifs recognized by several FHA domains, including those within a number of DNA damage checkpoint kinases, and determined the X-ray structure of Rad53p-FHA1, in complex with a phospho-threonine peptide, at 1.6 A resolution. The structure reveals a striking similarity to the MH2 domains of Smad tumor suppressor proteins and reveals a mode of peptide binding that differs from SH2, 14-3-3, or PTB domain complexes. These results have important implications for DNA damage signaling and CHK2-dependent tumor suppression, and they indicate that FHA domains play important and unsuspected roles in S/T kinase signaling mechanisms in prokaryotes and eukaryotes. |
| doi_str_mv | 10.1016/s1097-2765(00)00114-3 |
| format | Article |
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We have used oriented peptide library screening to determine the optimal phosphopeptide binding motifs recognized by several FHA domains, including those within a number of DNA damage checkpoint kinases, and determined the X-ray structure of Rad53p-FHA1, in complex with a phospho-threonine peptide, at 1.6 A resolution. The structure reveals a striking similarity to the MH2 domains of Smad tumor suppressor proteins and reveals a mode of peptide binding that differs from SH2, 14-3-3, or PTB domain complexes. 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We have used oriented peptide library screening to determine the optimal phosphopeptide binding motifs recognized by several FHA domains, including those within a number of DNA damage checkpoint kinases, and determined the X-ray structure of Rad53p-FHA1, in complex with a phospho-threonine peptide, at 1.6 A resolution. The structure reveals a striking similarity to the MH2 domains of Smad tumor suppressor proteins and reveals a mode of peptide binding that differs from SH2, 14-3-3, or PTB domain complexes. 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Taylor, I A ; Sarbassova, D ; Haire, L F ; Westcott, S L ; Jackson, S P ; Smerdon, S J ; Yaffe, M B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c501t-43eb80fc63e0d6a4c50fcdd68c868e436a092e17a374bbecc383b0fe91d076db3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>14-3-3 Proteins</topic><topic>Amino Acid Motifs</topic><topic>Amino Acid Sequence</topic><topic>Arginine - genetics</topic><topic>Arginine - metabolism</topic><topic>Binding Sites</topic><topic>Cell Cycle Proteins</topic><topic>Checkpoint Kinase 2</topic><topic>Crystallization</topic><topic>Crystallography, X-Ray</topic><topic>FHA1 protein</topic><topic>Forkhead Transcription Factors</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Mutation - genetics</topic><topic>Nuclear Proteins - chemistry</topic><topic>Peptide Library</topic><topic>Phosphopeptides - chemistry</topic><topic>Phosphopeptides - genetics</topic><topic>Phosphopeptides - metabolism</topic><topic>Phosphothreonine - chemistry</topic><topic>Phosphothreonine - metabolism</topic><topic>Protein Binding</topic><topic>Protein Interaction Mapping</topic><topic>Protein Kinases - chemistry</topic><topic>Protein Kinases - genetics</topic><topic>Protein Kinases - metabolism</topic><topic>Protein Structure, Secondary</topic><topic>Protein Structure, Tertiary</topic><topic>Protein-Serine-Threonine Kinases - chemistry</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Rad53 protein</topic><topic>Saccharomyces cerevisiae Proteins - chemistry</topic><topic>Saccharomyces cerevisiae Proteins - genetics</topic><topic>Saccharomyces cerevisiae Proteins - metabolism</topic><topic>Signal Transduction</topic><topic>src Homology Domains</topic><topic>Substrate Specificity</topic><topic>Transcription Factors - chemistry</topic><topic>Tyrosine 3-Monooxygenase - chemistry</topic><topic>Tyrosine 3-Monooxygenase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Durocher, D</creatorcontrib><creatorcontrib>Taylor, I A</creatorcontrib><creatorcontrib>Sarbassova, D</creatorcontrib><creatorcontrib>Haire, L F</creatorcontrib><creatorcontrib>Westcott, S L</creatorcontrib><creatorcontrib>Jackson, S P</creatorcontrib><creatorcontrib>Smerdon, S J</creatorcontrib><creatorcontrib>Yaffe, M B</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Durocher, D</au><au>Taylor, I A</au><au>Sarbassova, D</au><au>Haire, L F</au><au>Westcott, S L</au><au>Jackson, S P</au><au>Smerdon, S J</au><au>Yaffe, M B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2000-11-01</date><risdate>2000</risdate><volume>6</volume><issue>5</issue><spage>1169</spage><epage>1182</epage><pages>1169-1182</pages><issn>1097-2765</issn><abstract>Forkhead-associated (FHA) domains are a class of ubiquitous signaling modules that appear to function through interactions with phosphorylated target molecules. We have used oriented peptide library screening to determine the optimal phosphopeptide binding motifs recognized by several FHA domains, including those within a number of DNA damage checkpoint kinases, and determined the X-ray structure of Rad53p-FHA1, in complex with a phospho-threonine peptide, at 1.6 A resolution. The structure reveals a striking similarity to the MH2 domains of Smad tumor suppressor proteins and reveals a mode of peptide binding that differs from SH2, 14-3-3, or PTB domain complexes. These results have important implications for DNA damage signaling and CHK2-dependent tumor suppression, and they indicate that FHA domains play important and unsuspected roles in S/T kinase signaling mechanisms in prokaryotes and eukaryotes.</abstract><cop>United States</cop><pmid>11106755</pmid><doi>10.1016/s1097-2765(00)00114-3</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 14-3-3 Proteins Amino Acid Motifs Amino Acid Sequence Arginine - genetics Arginine - metabolism Binding Sites Cell Cycle Proteins Checkpoint Kinase 2 Crystallization Crystallography, X-Ray FHA1 protein Forkhead Transcription Factors Humans Models, Molecular Molecular Sequence Data Mutation - genetics Nuclear Proteins - chemistry Peptide Library Phosphopeptides - chemistry Phosphopeptides - genetics Phosphopeptides - metabolism Phosphothreonine - chemistry Phosphothreonine - metabolism Protein Binding Protein Interaction Mapping Protein Kinases - chemistry Protein Kinases - genetics Protein Kinases - metabolism Protein Structure, Secondary Protein Structure, Tertiary Protein-Serine-Threonine Kinases - chemistry Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Rad53 protein Saccharomyces cerevisiae Proteins - chemistry Saccharomyces cerevisiae Proteins - genetics Saccharomyces cerevisiae Proteins - metabolism Signal Transduction src Homology Domains Substrate Specificity Transcription Factors - chemistry Tyrosine 3-Monooxygenase - chemistry Tyrosine 3-Monooxygenase - metabolism |
| title | The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms |
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