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  • 1
    Publication Date: 2003-10-25
    Description: We used a proteomic approach to identify phosphopeptide-binding modules mediating signal transduction events in the DNA damage response pathway. Using a library of partially degenerate phosphopeptides, we identified tandem BRCT (BRCA1 carboxyl-terminal) domains in PTIP (Pax transactivation domain-interacting protein) and in BRCA1 as phosphoserine- or phosphothreonine-specific binding modules that recognize substrates phosphorylated by the kinases ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia- and RAD3-related) in response to gamma-irradiation. PTIP tandem BRCT domains are responsible for phosphorylation-dependent protein localization into 53BP1- and phospho-H2AX (gamma-H2AX)-containing nuclear foci, a marker of DNA damage. These findings provide a molecular basis for BRCT domain function in the DNA damage response and may help to explain why the BRCA1 BRCT domain mutation Met1775 --〉 Arg, which fails to bind phosphopeptides, predisposes women to breast and ovarian cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Manke, Isaac A -- Lowery, Drew M -- Nguyen, Anhco -- Yaffe, Michael B -- GM60594/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2003 Oct 24;302(5645):636-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/14576432" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Ataxia Telangiectasia Mutated Proteins ; BRCA1 Protein/*chemistry/*metabolism ; Caffeine/pharmacology ; Calorimetry ; Carrier Proteins/*chemistry/*metabolism ; Cell Cycle Proteins/antagonists & inhibitors/metabolism ; Cell Nucleus/metabolism ; Cytosol/metabolism ; DNA Damage ; DNA-Binding Proteins ; Gamma Rays ; Humans ; Nuclear Proteins/*chemistry/*metabolism ; Peptide Library ; Phosphopeptides/*metabolism ; Phosphorylation ; Phosphoserine/metabolism ; Phosphothreonine/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Proteomics ; Signal Transduction ; Tumor Cells, Cultured ; Tumor Suppressor Proteins
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2003-02-22
    Description: We have developed a proteomic approach for identifying phosphopeptide binding domains that modulate kinase-dependent signaling pathways. An immobilized library of partially degenerate phosphopeptides biased toward a particular protein kinase phosphorylation motif is used to isolate phospho-binding domains that bind to proteins phosphorylated by that kinase. Applying this approach to cyclin-dependent kinases (Cdks), we identified the polo-box domain (PBD) of the mitotic kinase polo-like kinase 1 (Plk1) as a specific phosphoserine (pSer) or phosphothreonine (pThr) binding domain and determined its optimal binding motif. This motif is present in known Plk1 substrates such as Cdc25, and an optimal phosphopeptide containing the motif disrupted PBD-substrate binding and localization of the PBD to centrosomes. This finding reveals how Plk1 can localize to specific sites within cells in response to Cdk phosphorylation at those sites and provides a structural mechanism for targeting the Plk1 kinase domain to its substrates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Elia, Andrew E H -- Cantley, Lewis C -- Yaffe, Michael B -- GM52981/GM/NIGMS NIH HHS/ -- GM56203/GM/NIGMS NIH HHS/ -- R01 GM056203/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2003 Feb 21;299(5610):1228-31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12595692" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Binding Sites ; Calorimetry ; Cell Cycle Proteins ; Centrosome/metabolism ; HeLa Cells ; Humans ; Ligands ; Mitosis ; Peptide Library ; Phosphopeptides/chemistry/*metabolism ; Phosphorylation ; Phosphoserine/*metabolism ; Phosphothreonine/*metabolism ; Point Mutation ; Protein Binding ; Protein Kinases/*chemistry/genetics/*metabolism ; *Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases ; Proteomics ; Proto-Oncogene Proteins ; Signal Transduction ; cdc25 Phosphatases/chemistry/genetics/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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