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Mechanisms of dynamic +TIP interactions

English title Mechanisms of dynamic +TIP interactions
Applicant Steinmetz Michel
Number 122545
Funding scheme Project funding (Div. I-III)
Research institution Paul Scherrer Institut
Institution of higher education Paul Scherrer Institute - PSI
Main discipline Biochemistry
Start/End 01.01.2009 - 31.12.2011
Approved amount 840'000.00
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Keywords (9)

microtubule; microtubule-associated-proteins; microtubule plus end tracking proteins (+TIPs); structure-function relationship; protein-protein interactions; x-ray crystography; biochemistry; biophysics; cell biology

Lay Summary (English)

Lead
Lay summary
Laysummary: Microtubule plus end tracking protein (+TIP) networks play a pivotal role in all microtubule-based cellular processes including chromosome segregation, vesicle and organelle transport, delivery of proteins to the cell periphery, establishment and maintenance of cell polarity, and cell migration. Although many studies have revealed the central components forming +TIP networks, the detailed nature, specificity, and regulation modes of their dynamic interactions are largely unknown. As a consequence, the molecular mechanisms underlying the phenomenon of microtubule plus end tracking and microtubule end capturing of cellular structures by the +TIP machinery are poorly understood. In this project, we propose to investigate key factors that define and regulate the +TIP interactome with the aim to provide detailed quantitative, structural and functional information for understanding +TIP network behavior at the systems level. To reach this goal we will use an integrated experimental approach encompassing cell biological, biochemical, biophysical and structural methods. We expect that the results of the proposed work will afford a comprehensive, molecular view of a well-defined, biologically and medically important dynamic protein network. We further anticipate that the planned studies will deliver a firm conceptual and experimental basis for extending the research towards assessing the next level of complexity: the mechanisms by which the mammalian +TIP machinery targets microtubule ends to specific cellular structures such as membrane compartments, the cell cortex and kinetochores.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Insights into EB1 structure and the role of its C-terminal domain for discriminating microtubule tips from the lattice.
Buey Rubén M, Mohan Renu, Leslie Kris, Walzthoeni Thomas, Missimer John H, Menzel Andreas, Bjelic Saša, Bargsten Katja, Grigoriev Ilya, Smal Ihor, Meijering Erik, Aebersold Ruedi, Akhmanova Anna, Steinmetz Michel O (2011), Insights into EB1 structure and the role of its C-terminal domain for discriminating microtubule tips from the lattice., in Molecular biology of the cell, 22(16), 2912-23.
Microtubule end binding: EBs sense the guanine nucleotide state.
Akhmanova Anna, Steinmetz Michel O (2011), Microtubule end binding: EBs sense the guanine nucleotide state., in Current biology : CB, 21(8), 283-285.
SLAIN2 links microtubule plus end-tracking proteins and controls microtubule growth in interphase.
van der Vaart Babet, Manatschal Cristina, Grigoriev Ilya, Olieric Vincent, Gouveia Susana Montenegro, Bjelic Sasa, Demmers Jeroen, Vorobjev Ivan, Hoogenraad Casper C, Steinmetz Michel O, Akhmanova Anna (2011), SLAIN2 links microtubule plus end-tracking proteins and controls microtubule growth in interphase., in The Journal of cell biology, 193(6), 1083-99.
In vitro reconstitution of the functional interplay between MCAK and EB3 at microtubule plus ends.
Montenegro Gouveia Susana, Leslie Kris, Kapitein Lukas C, Buey Rubén M, Grigoriev Ilya, Wagenbach Michael, Smal Ihor, Meijering Erik, Hoogenraad Casper C, Wordeman Linda, Steinmetz Michel O, Akhmanova Anna (2010), In vitro reconstitution of the functional interplay between MCAK and EB3 at microtubule plus ends., in Current biology : CB, 20(19), 1717-22.
Microtubule +TIPs at a glance.
Akhmanova Anna, Steinmetz Michel O (2010), Microtubule +TIPs at a glance., in Journal of cell science, 123(Pt 20), 3415-9.
Molecular insights into mammalian end-binding protein heterodimerization.
De Groot Christian O, Jelesarov Ilian, Damberger Fred F, Bjelić Sasa, Schärer Martin A, Bhavesh Neel S, Grigoriev Ilia, Buey Ruben M, Wüthrich Kurt, Capitani Guido, Akhmanova Anna, Steinmetz Michel O (2010), Molecular insights into mammalian end-binding protein heterodimerization., in The Journal of biological chemistry, 285(8), 5802-14.
An EB1-binding motif acts as a microtubule tip localization signal.
Honnappa Srinivas, Gouveia Susana Montenegro, Weisbrich Anke, Damberger Fred F, Bhavesh Neel S, Jawhari Hatim, Grigoriev Ilya, van Rijssel Frederik J A, Buey Ruben M, Lawera Aleksandra, Jelesarov Ilian, Winkler Fritz K, Wüthrich Kurt, Akhmanova Anna, Steinmetz Michel O (2009), An EB1-binding motif acts as a microtubule tip localization signal., in Cell, 138(2), 366-76.
Capturing protein tails by CAP-Gly domains.
Steinmetz Michel O, Akhmanova Anna (2009), Capturing protein tails by CAP-Gly domains., in Trends in biochemical sciences, 33(11), 535-545.
Mammalian end binding proteins control persistent microtubule growth.
Komarova Yulia, De Groot Christian O, Grigoriev Ilya, Gouveia Susana Montenegro, Munteanu E Laura, Schober Joseph M, Honnappa Srinivas, Buey Rubén M, Hoogenraad Casper C, Dogterom Marileen, Borisy Gary G, Steinmetz Michel O, Akhmanova Anna (2009), Mammalian end binding proteins control persistent microtubule growth., in The Journal of cell biology, 184(5), 691-706.
Regulation of microtubule dynamic instability in vitro by differentially phosphorylated stathmin.
Manna Tapas, Thrower Douglas A, Honnappa Srinivas, Steinmetz Michel O, Wilson Leslie (2009), Regulation of microtubule dynamic instability in vitro by differentially phosphorylated stathmin., in The Journal of biological chemistry, 284(23), 15640-9.
ELM--the database of eukaryotic linear motifs.
Dinkel Holger, Michael Sushama, Weatheritt Robert J, Davey Norman E, Van Roey Kim, Altenberg Brigitte, Toedt Grischa, Uyar Bora, Seiler Markus, Budd Aidan, Jödicke Lisa, Dammert Marcel A, Schroeter Christian, Hammer Maria, Schmidt Tobias, Jehl Peter, McGuigan Caroline, Dymecka Magdalena, Chica Claudia, Luck Katja, Via Allegra, Chatr-Aryamontri Andrew, Haslam Niall, Grebnev Gleb, Edwards Richard J, ELM--the database of eukaryotic linear motifs., in Nucleic acids research.
Interaction of mammalian end binding proteins with CAP-Gly domains of CLIP-170 and p150(glued).
Bjelić Saša, De Groot Christian O, Schärer Martin A, Jaussi Rolf, Bargsten Katja, Salzmann Mara, Frey Daniel, Capitani Guido, Kammerer Richard A, Steinmetz Michel O, Interaction of mammalian end binding proteins with CAP-Gly domains of CLIP-170 and p150(glued)., in Journal of structural biology.

Collaboration

Group / person Country
Types of collaboration
Kurt Wüthrich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Toby Gibson Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Rudolf Aebersold Switzerland (Europe)
- Publication
Leslie Wilson United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Richard Kammerer Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Rudolf Volkmer Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Anna Akhmanova Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual meeting of the ameriacn society of nephrology Talk given at a conference Mechanisms of centriole duplication 10.11.2011 Philadelphiy, United States of America Steinmetz Michel;
EMBO members meeting Talk given at a conference Mechanisms of centriole duplication 26.10.2011 Heidelberg, Germany Steinmetz Michel;
INSERM workshop #206 Talk given at a conference Mechanisms of microtubule tip tracking 16.09.2010 Saint-Raphaël, France Steinmetz Michel;
Workshop on biomolecular interactions by experimental methods Talk given at a conference Mechanisms of microtubule tip tracking 04.11.2009 Brno, Czech Republic Steinmetz Michel;
FEBS Workshop on protein modules and networks in health and disease Talk given at a conference Mechanisms of centriole formation 10.09.2009 Seefeld in Tirol, Austria Steinmetz Michel;
Alpbach Workshop 2009 on coiled coils, collagen and co-proteins Talk given at a conference Mechanisms of centriole formation 07.09.2009 Alpbach, Austria Steinmetz Michel;
The EMBO Meeting Talk given at a conference Mechanisms of microtubule tip tracking 29.08.2009 Amsterdam, Netherlands Steinmetz Michel;


Self-organised

Title Date Place
EMBO Conference Series, Microtubules - Structure, Regulation and Functions 04.07.2010 Heidelberg, Germany

Awards

Title Year
EMBO member 2010

Associated projects

Number Title Start Funding scheme
133810 Upgrading the biophysical facility at PSI with analytical ultracentrifuge equipped with fluorescence detection system. 01.12.2010 R'EQUIP
121315 Upgrading the light microscopy facility at PSI with total internal reflection fluorescence microscopy (TIRFM) 01.07.2008 R'EQUIP
138659 Protein interactions regulating the microtubule cytoskeleton 01.01.2012 Project funding (Div. I-III)
109423 Mechanisms for protein-protein interactions regulating microtubule dynamics 01.01.2006 Project funding (Div. I-III)

Abstract

Microtubule plus end tracking protein (+TIP) networks play a pivotal role in all microtubule-based cellular processes including chromosome segregation, vesicle and organelle transport, delivery of proteins to the cell periphery, establishment and maintenance of cell polarity, and cell migration. Although many studies have revealed the central components forming +TIP networks, the detailed nature, specificity, and regulation modes of their dynamic interactions are largely unknown. As a consequence, the molecular mechanisms underlying the phenomenon of microtubule plus end tracking and microtubule end capturing of cellular structures by the +TIP machinery are poorly understood. In this project, we propose to investigate key factors that define and regulate the +TIP interactome with the aim to provide detailed quantitative, structural and functional information for understanding +TIP network behavior at the system level. To reach this goal we will use an integrated experimental approach encompassing cell biological, biochemical and biophysical methods. We expect that the results of the proposed work will afford a comprehensive, molecular view of a well-defined, biologically and medically important dynamic protein network. We further anticipate that the planned studies will deliver a firm conceptual and experimental basis for extending the research towards assessing the next level of complexity: the mechanisms by which the mammalian +TIP machinery targets microtubule ends to specific cellular structures such as membrane compartments, the cell cortex and kinetochores.
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