Structural determinants of RhoA binding and nucleotide exchange in leukemia-associated Rho guanine-nucleotide exchange factor.

The Journal of Biological Chemistry
Romana KristellyJohn J G Tesmer

Abstract

Rho guanine-nucleotide exchange factors (RhoGEFs) activate Rho GTPases, and thereby regulate cytoskeletal structure, gene transcription, and cell migration. Leukemia-associated RhoGEF (LARG) belongs to a small subfamily of RhoGEFs that are RhoA-selective and directly activated by the Galpha12/13 family of heterotrimeric G proteins. Herein we describe the atomic structures of the catalytic Dbl homology (DH) and pleckstrin homology (PH) domains of LARG alone and in complex with RhoA. These structures demonstrate that the DH/PH domains of LARG can undergo a dramatic conformational change upon binding RhoA, wherein both the DH and PH domains directly engage RhoA. Through mutational analysis we show that full nucleotide exchange activity requires a novel N-terminal extension on the DH domain that is predicted to exist in a broader family of RhoGEFs that includes p115-RhoGEF, Lbc, Lfc, Net1, and Xpln, and identify regions within the LARG PH domain that contribute to its ability to facilitate nucleotide exchange in vitro. In crystals of the DH/PH-RhoA complex, the active site of RhoA adopts two distinct GDP-excluding conformations among the four unique complexes in the asymmetric unit. Similar changes were previously observed in struc...Continue Reading

References

Mar 1, 1991·Acta Crystallographica. Section A, Foundations of Crystallography·T A JonesM Kjeldgaard
Jul 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·D J ClantonT Y Shih
Mar 1, 1997·Nature Structural Biology·K Djinovic CarugoM Saraste
Aug 1, 1997·Nature Structural Biology·Y WangP B Sigler
Jan 7, 1998·Oncogene·M F OlsonA Hall
Jun 26, 1998·Science·T KozasaP C Sternweis
Aug 5, 1998·Nature·P A Boriack-SjodinJ Kuriyan
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Oct 19, 1999·Molecular and Cellular Biology·I P WhiteheadC J Der
Oct 19, 2000·Methods in Enzymology·K L Rossman, S L Campbell
Jan 3, 2001·Acta Crystallographica. Section D, Biological Crystallography·M D WinnG N Murshudov
Apr 21, 2001·Oncogene·I P WhiteheadC J Der
Oct 31, 2001·Nature Structural Biology·A E KarnoubC J Der
Mar 9, 2002·Advances in Cancer Research·Aron B Jaffe, Alan Hall
May 15, 2002·Nature Structural Biology·Jason T SnyderJohn Sondek
May 25, 2002·Molecular and Cellular Biology·Michelle A BoodenChanning J Der
Jul 9, 2002·Genes & Development·Anja Schmidt, Alan Hall
Aug 15, 2002·The Journal of Biological Chemistry·Todd R PalmbyChanning J Der
Sep 11, 2002·The Journal of Biological Chemistry·William T ArthurKrister Wennerberg
Dec 13, 2002·Nature·Sandrine Etienne-Manneville, Alan Hall
Jan 8, 2003·Proceedings of the National Academy of Sciences of the United States of America·Nobuchika SuzukiTohru Kozasa
Mar 15, 2003·Nature Reviews. Cancer·Erik Sahai, Christopher J Marshall
Mar 15, 2003·The Journal of Biological Chemistry·Kent L RossmanJohn Sondek
Mar 15, 2003·The Journal of Biological Chemistry·Ernesto J FuentesSharon L Campbell
Jul 15, 2003·The Journal of Biological Chemistry·Ikuko Hayashi, Mitsuhiko Ikura
Sep 23, 2003·Acta Crystallographica. Section D, Biological Crystallography·Romana KristellyJohn J G Tesmer
Jan 15, 2004·Biology of the Cell·J-M BellangerA Debant
Jun 17, 2004·The Journal of Biological Chemistry·Karlheinz R SkowronekNicolas Nassar
Jul 28, 2004·Structure·David K WorthylakeJohn Sondek
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4

❮ Previous
Next ❯

Citations

Apr 9, 2005·Trends in Biochemical Sciences·Kent L Rossman, John Sondek
Feb 3, 2005·Nature Reviews. Molecular Cell Biology·Kent L RossmanJohn Sondek
Oct 3, 2012·Proceedings of the National Academy of Sciences of the United States of America·Akiyoshi UezuScott H Soderling
Feb 6, 2013·Proceedings of the National Academy of Sciences of the United States of America·Xun ShangYi Zheng
Oct 22, 2009·The Journal of Biological Chemistry·Changkeun LeeDean R Appling
Dec 19, 2009·The Journal of Biological Chemistry·Geneviève M C Gasmi-SeabrookMitsuhiko Ikura
Aug 6, 2011·The Journal of Biological Chemistry·Jakub A BielnickiZygmunt S Derewenda
Jun 5, 2012·The Journal of Biological Chemistry·Zhe ChenPaul C Sternweis
Dec 17, 2008·The Journal of Biological Chemistry·Nobuchika SuzukiTohru Kozasa
Aug 30, 2011·Journal of Biochemistry·Tohru KozasaNobuchika Suzuki
Nov 30, 2012·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Kazutaka MurayamaMikako Shirouzu
Nov 3, 2009·Molecular Pharmacology·Mohamed AittalebJohn J G Tesmer
May 18, 2007·Annual Review of Biochemistry·Atlanta CookElena Conti
Mar 6, 2012·BMC Bioinformatics·Donny SohLimsoon Wong
Jan 12, 2007·Biological Chemistry·Katja Gotthardt, Mohammad Reza Ahmadian
Nov 24, 2006·Proceedings of the National Academy of Sciences of the United States of America·Adrian W R SerohijosNikolay V Dokholyan
May 10, 2007·Proceedings of the National Academy of Sciences of the United States of America·Yusuke SatoOsamu Nureki
Dec 25, 2012·Experimental Cell Research·Jakob Nikolas Kather, Jens Kroll
Jun 5, 2012·Protein Expression and Purification·Colin A HigginsDavid L Roman
Mar 30, 2007·Journal of Molecular Biology·Mariya K ChhatriwalaJohn Sondek
Aug 12, 2009·Protein Science : a Publication of the Protein Society·Tomasz CierpickiZygmunt S Derewenda
Jul 11, 2009·Protein Science : a Publication of the Protein Society·Manoj TyagiAnna R Panchenko
May 31, 2008·EMBO Reports·Jonathan RapleyKatrin Rittinger
Nov 11, 2010·Protein Science : a Publication of the Protein Society·Zhe ChenPaul C Sternweis
Sep 16, 2010·Protein Science : a Publication of the Protein Society·Carsten KintscherYvonne Groemping
Jul 22, 2014·Genes, Chromosomes & Cancer·Marius RohdeUNKNOWN NHL-BFM Study Group
Dec 9, 2014·Small GTPases·Antje SchaeferPeter L Hordijk
Jul 12, 2012·Advances in Biological Regulation·Julien ViaudBernard Payrastre
Sep 5, 2014·The Biochemical Journal·Kamal R Abdul AzeezJonathan M Elkins
Jun 8, 2012·Small GTPases·Christina M SloanShawn M Ellerbroek
Jan 1, 2013·Cell Adhesion & Migration·Maulik Patel, Andrei V Karginov

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.