The SH2 Domain Regulates c-Abl Kinase Activation by a Cyclin-Like Mechanism and Remodulation of the Hinge Motion
Publication Date
October 09, 2014
Journal
PLOS Computational Biology
Authors
Nicole Dölker, Maria W. Górna, Ludovico Sutto, Antonio S. Torralba, et al
Volume
10
Issue
10
Pages
e1003863
DOI
https://dx.plos.org/10.1371/journal.pcbi.1003863
Publisher URL
http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1003863
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/25299346
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191882
Europe PMC
http://europepmc.org/abstract/MED/25299346
Web of Science
000344547900019
Scopus
84908348822
Mendeley
http://www.mendeley.com/research/sh2-domain-regulates-cabl-kinase-activation-cyclinlike-mechanism-remodulation-hinge-motion
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Mendeley | Further Information

{"title"=>"The SH2 Domain Regulates c-Abl Kinase Activation by a Cyclin-Like Mechanism and Remodulation of the Hinge Motion", "type"=>"journal", "authors"=>[{"first_name"=>"Nicole", "last_name"=>"Dölker", "scopus_author_id"=>"6507366766"}, {"first_name"=>"Maria W.", "last_name"=>"Górna", "scopus_author_id"=>"24558815400"}, {"first_name"=>"Ludovico", "last_name"=>"Sutto", "scopus_author_id"=>"23393975500"}, {"first_name"=>"Antonio S.", "last_name"=>"Torralba", "scopus_author_id"=>"7005432732"}, {"first_name"=>"Giulio", "last_name"=>"Superti-Furga", "scopus_author_id"=>"35355356900"}, {"first_name"=>"Francesco L.", "last_name"=>"Gervasio", "scopus_author_id"=>"6603509498"}], "year"=>2014, "source"=>"PLoS Computational Biology", "identifiers"=>{"issn"=>"15537358", "pui"=>"600311085", "doi"=>"10.1371/journal.pcbi.1003863", "sgr"=>"84908348822", "scopus"=>"2-s2.0-84908348822", "isbn"=>"10.1371/journal.pcbi.1003863", "pmid"=>"25299346"}, "id"=>"45758365-40fa-395c-adb4-e38af6ac40c7", "abstract"=>"Regulation of the c-Abl (ABL1) tyrosine kinase is important because of its role in cellular signaling, and its relevance in the leukemiogenic counterpart (BCR-ABL). Both auto-inhibition and full activation of c-Abl are regulated by the interaction of the catalytic domain with the Src Homology 2 (SH2) domain. The mechanism by which this interaction enhances catalysis is not known. We combined computational simulations with mutagenesis and functional analysis to find that the SH2 domain conveys both local and global effects on the dynamics of the catalytic domain. Locally, it regulates the flexibility of the αC helix in a fashion reminiscent of cyclins in cyclin-dependent kinases, reorienting catalytically important motifs. At a more global level, SH2 binding redirects the hinge motion of the N and C lobes and changes the conformational equilibrium of the activation loop. The complex network of subtle structural shifts that link the SH2 domain with the activation loop and the active site may be partially conserved with other SH2-domain containing kinases and therefore offer additional parameters for the design of conformation-specific inhibitors.", "link"=>"http://www.mendeley.com/research/sh2-domain-regulates-cabl-kinase-activation-cyclinlike-mechanism-remodulation-hinge-motion", "reader_count"=>35, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>9, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>15, "Student > Postgraduate"=>2, "Student > Master"=>3, "Student > Bachelor"=>2, "Unspecified"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>9, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>15, "Student > Postgraduate"=>2, "Student > Master"=>3, "Student > Bachelor"=>2, "Unspecified"=>2}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>3, "Materials Science"=>1, "Agricultural and Biological Sciences"=>19, "Medicine and Dentistry"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Chemistry"=>6, "Computer Science"=>1, "Unspecified"=>2}, "reader_count_by_subdiscipline"=>{"Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>6}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>19}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"United States"=>1, "Taiwan"=>1, "United Kingdom"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711268/Figure_1.tif"], "description"=>"<p><b>A</b> The c-Abl isoform Ib is characterized by myristoylation (Myr) on Gly-2 of the N-terminal capping region (cap). The tyrosine kinase domain is preceded by the SH3 and SH2 domains and a connecting linker. The last exon region contains nuclear localization signals and a C-terminal actin binding domain (ABD). <b>B</b> In the down-regulated state (PDB entry 2FO0), the SH2 domain binds the C-lobe of the kinase domain, the myristate is bound in its cognate pocket and the SH3 domain binds the SH2-CD linker. <b>C</b> In the active “top-hat” conformation (PDB entry 1OPL), the SH2 domain moves to interact with the N-lobe of the kinase domain. The αC helix and the activation loop are highlighted in red and pink, respectively. <b>D</b> Positions of the most important point mutations at the SH2-CD interface and in the β3-αC loop.</p>", "links"=>[], "tags"=>["SH 2 domain", "kinase", "SH 2 binding redirects", "Hinge Motion Regulation", "abl", "activation loop", "Src Homology 2"], "article_id"=>1198991, "categories"=>["Uncategorised"], "users"=>["Nicole Dölker", "Maria W. Górna", "Ludovico Sutto", "Antonio S. Torralba", "Giulio Superti-Furga", "Francesco L. Gervasio"], "doi"=>["http://dx.doi.org/10.1371/journal.pcbi.1003863.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Domain_organization_and_crystal_structures_of_Abl_kinase_/1198991", "title"=>"Domain organization and crystal structures of Abl kinase.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-09 03:21:16"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711269/Figure_2.tif"], "description"=>"<p><b>A</b> Allosteric couplings of residues in the CD to the SH2 domain. High values (yellow and red) indicate strong allosteric interactions (See also Supplemental <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003863#pcbi.1003863.s001\" target=\"_blank\">Figure S1</a> A–C). <b>B</b> Free CD colored by RMSF from MD simulations. <b>C</b> SH2-CD construct colored by RMSF. (See also <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003863#pcbi.1003863.s002\" target=\"_blank\">Figure S2</a>).</p>", "links"=>[], "tags"=>["SH 2 domain", "kinase", "SH 2 binding redirects", "Hinge Motion Regulation", "abl", "activation loop", "Src Homology 2"], "article_id"=>1198992, "categories"=>["Uncategorised"], "users"=>["Nicole Dölker", "Maria W. Górna", "Ludovico Sutto", "Antonio S. Torralba", "Giulio Superti-Furga", "Francesco L. Gervasio"], "doi"=>["http://dx.doi.org/10.1371/journal.pcbi.1003863.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Allosteric_coupling_and_flexibility_of_c_Abl_/1198992", "title"=>"Allosteric coupling and flexibility of c-Abl.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-09 03:21:16"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711280/Figure_3.tif"], "description"=>"<p><b>A</b> Range of conformations explored by SH2-CD. The crystal structure is shown in red, the predominant conformation from the simulation in orange. Other representative structures from the trajectory are shown in grey. <b>B</b> Close up on the most representative structure of the CD and the CD-SH2 complex. <b>C</b> Distance between E305(Cδ) and K290(Nζ). The average values, calculated for the last 750 ns of simulation time, are marked by cyan (CD) and orange (SH2-CD) lines and labelled with the corresponding values (in nm). <b>D</b> Projection of the trajectories of the CD in absence and presence of SH2 on the two dominant eigenvectors from the principal component analysis of the trajectory of the free CD. <b>E</b> Eigenvalue spectrum for the CD and the SH2-CD constructs. (See also Figures S1 and S3).</p>", "links"=>[], "tags"=>["SH 2 domain", "kinase", "SH 2 binding redirects", "Hinge Motion Regulation", "abl", "activation loop", "Src Homology 2"], "article_id"=>1198994, "categories"=>["Uncategorised"], "users"=>["Nicole Dölker", "Maria W. Górna", "Ludovico Sutto", "Antonio S. Torralba", "Giulio Superti-Furga", "Francesco L. Gervasio"], "doi"=>["http://dx.doi.org/10.1371/journal.pcbi.1003863.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Conformational_plasticity_and_essential_dynamics_of_c_Abl_/1198994", "title"=>"Conformational plasticity and essential dynamics of c-Abl.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-09 03:21:16"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711294/Figure_4.tif"], "description"=>"<p>The free energy surfaces of the A-loop transition from open (active-like) to closed (inactive-like) conformation in case of the ABL catalytic domain alone (left) and in presence of the SH2 regulatory domain in the “top-hat” conformation as a function of the contact map distances to the respective reference structures. For the deepest minima a representative structure is also shown below with the CD colored in blue, the SH2 in green, the A-loop in yellow and the aC-helix in red.</p>", "links"=>[], "tags"=>["SH 2 domain", "kinase", "SH 2 binding redirects", "Hinge Motion Regulation", "abl", "activation loop", "Src Homology 2"], "article_id"=>1199008, "categories"=>["Uncategorised"], "users"=>["Nicole Dölker", "Maria W. Górna", "Ludovico Sutto", "Antonio S. Torralba", "Giulio Superti-Furga", "Francesco L. Gervasio"], "doi"=>["http://dx.doi.org/10.1371/journal.pcbi.1003863.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_The_free_energy_of_conformational_changes_of_the_A_loop_/1199008", "title"=>"The free energy of conformational changes of the A-loop.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-09 03:21:16"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711297/Figure_5.tif"], "description"=>"<p>Abl proteins were immunoprecipitated and assayed for phosphorylation of an optimal Abl substrate peptide. The kinase activity was normalized to the amount of protein and to the activity of the wild-type CD or SH2-CD construct. <b>A</b> M297L was found to decrease kinase activity, whereas M297G had an activating effect in the absence of the SH2 domain. The kinase-dead mutant D382N presented no activity, and the known inactivating (I164E) and activating (T231R) mutations also show, accordingly, a decreased and increased activity. <b>B</b> The M297G mutant is significantly more active in the context of the isolated kinase domain, but not in the presence of the SH2 domain. The error bars are standard deviations from biological quadruplicates (n = 4, **P<0.01, Student <i>t</i> test). <b>C</b> Mutations E294P and E294P V299P have an activating effect. The reactions were performed at 37°C. <b>D</b> The activity of wild-type and E294P V299P Abl proteins was measured at increasing substrate concentrations and 25 µM ATP. <b>E</b> Y339G substitution is neutral, whereas Y339P diminishes Abl activity. The effect is seen both at 24°C and at an elevated temperature. <b>F, G</b> The ratio of the kinase activity at the elevated and room temperatures. Except for Y339P, the SH2-CD proteins retain their activity at the elevated temperature, whereas the activity of the CD constructs is reduced at least 2-fold. The error bars are standard deviations from technical triplicates except for (B). (See also Figures S4 and S5).</p>", "links"=>[], "tags"=>["SH 2 domain", "kinase", "SH 2 binding redirects", "Hinge Motion Regulation", "abl", "activation loop", "Src Homology 2"], "article_id"=>1199010, "categories"=>["Uncategorised"], "users"=>["Nicole Dölker", "Maria W. Górna", "Ludovico Sutto", "Antonio S. Torralba", "Giulio Superti-Furga", "Francesco L. Gervasio"], "doi"=>["http://dx.doi.org/10.1371/journal.pcbi.1003863.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Effect_of_point_mutations_on_the_kinase_activity_of_c_Abl_/1199010", "title"=>"Effect of point mutations on the kinase activity of c-Abl.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-09 03:21:16"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711299/Table_1.xls"], "description"=>"<p>Mutants were tested for c-Abl activity via immunoblotting of HEK293 lysates or immunoprecipitates (IP) and via kinase activity assay. The numbering of residues is in agreement with the sequence of the isoform Ib. Activity scoring (effect of the mutation):, nt, not tested, − inactive (mutation disruptive), + weakly active (mutation mildly disruptive), ++ activity similar to wild-type (mutation neutral), +++ hyperactive (mutation activating) (See also Supplemental Table S1).</p><p>List of c-Abl point mutants investigated in this study with summary of the effect of mutations.</p>", "links"=>[], "tags"=>["SH 2 domain", "kinase", "SH 2 binding redirects", "Hinge Motion Regulation", "abl", "activation loop", "Src Homology 2"], "article_id"=>1199012, "categories"=>["Uncategorised"], "users"=>["Nicole Dölker", "Maria W. Górna", "Ludovico Sutto", "Antonio S. Torralba", "Giulio Superti-Furga", "Francesco L. Gervasio"], "doi"=>["http://dx.doi.org/10.1371/journal.pcbi.1003863.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_List_of_c_Abl_point_mutants_investigated_in_this_study_with_summary_of_the_effect_of_mutations_/1199012", "title"=>"List of c-Abl point mutants investigated in this study with summary of the effect of mutations.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-10-09 03:21:16"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711413/Figure_S1.eps", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711414/Figure_S2.eps", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711415/Figure_S3.eps", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711417/Figure_S4.tif", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711418/Figure_S5.eps", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711419/Figure_S6.eps", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711420/Figure_S7.eps", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711421/Figure_S8.eps", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/1711423/Text_S1.pdf"], "description"=>"<div><p>Regulation of the c-Abl (ABL1) tyrosine kinase is important because of its role in cellular signaling, and its relevance in the leukemiogenic counterpart (BCR-ABL). Both auto-inhibition and full activation of c-Abl are regulated by the interaction of the catalytic domain with the Src Homology 2 (SH2) domain. The mechanism by which this interaction enhances catalysis is not known. We combined computational simulations with mutagenesis and functional analysis to find that the SH2 domain conveys both local and global effects on the dynamics of the catalytic domain. Locally, it regulates the flexibility of the αC helix in a fashion reminiscent of cyclins in cyclin-dependent kinases, reorienting catalytically important motifs. At a more global level, SH2 binding redirects the hinge motion of the N and C lobes and changes the conformational equilibrium of the activation loop. The complex network of subtle structural shifts that link the SH2 domain with the activation loop and the active site may be partially conserved with other SH2-domain containing kinases and therefore offer additional parameters for the design of conformation-specific inhibitors.</p></div>", "links"=>[], "tags"=>["SH 2 domain", "kinase", "SH 2 binding redirects", "Hinge Motion Regulation", "abl", "activation loop", "Src Homology 2"], "article_id"=>1199095, "categories"=>["Uncategorised"], "users"=>["Nicole Dölker", "Maria W. Górna", "Ludovico Sutto", "Antonio S. Torralba", "Giulio Superti-Furga", "Francesco L. Gervasio"], "doi"=>["http://dx.doi.org/10.1371/journal.pcbi.1003863"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_The_SH2_Domain_Regulates_c_Abl_Kinase_Activation_by_a_Cyclin_Like_Mechanism_and_Remodulation_of_the_Hinge_Motion_/1199095", "title"=>"The SH2 Domain Regulates c-Abl Kinase Activation by a Cyclin-Like Mechanism and Remodulation of the Hinge Motion", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-10-09 03:21:16"}

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