Összes szerző

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az alábbi absztraktok szerzői között szerepel:

Czigléczki Janka Zsófia
Functionally important C-terminus of small GTPase Ran: exploring its nucleotide-specific conformational surface

Aug 30 - szerda

15:30 – 17:00

II. Poszterszekció

P39

Functionally important C-terminus of small GTPase Ran: exploring its nucleotide-specific conformational surface

Janka Czigleczki1, Pedro Tulio de Resende Lara2, Balint Dudas1,3,4, Hyunbum Jang5, David Perahia4, Ruth Nussinov 5,6and Erika Balog1

1Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary

2Department of Medical Genetics and Genomic Medicine, School of Medical Sciences, University of Campinas—UNICAMP, Campinas, Brazil 

3Inserm U1268 MCTR, CiTCoM UMR 8038 CNRS—Université Paris Cité, Paris, France

4Laboratoire et Biologie et Pharmacologie Appliquée, Ecole Normale Supérieure Paris-Saclay, Gif-sur-Yvette, France

5Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD, United States

6Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

As a member of the Ras superfamily of small GTPases, Ran (Ras-related Nuclear protein) is the main regulator of the nucleo-cytoplasmic transport through the nuclear core complex. It functions as a molecular switch cycling between the GDP-bound inactive or “off” and GTP-bound active or “on” state. Since deregulation of Ran is linked to numerous cancers from the stage of cancer initiation to metastasis, understanding the complexity of its interaction, especially the regulatory mechanism, is critical for drug discovery.

 Ran consists of a globular (G) domain and a C-terminal region, which is bound to the G-domain in the inactive, GDP-bound states. The crystal structures of the GTP-bound active form complexed with Ran binding proteins (RanBP) show that the C-terminus undergoes a large conformational change, embracing Ran binding domains (RanBD), whereas in the crystal structures of macromolecular complexes not containing RanBDs the structure of the C-terminal segment remains unresolved, indicating its large conformational flexibility. This movement could not have been followed either by experimental or simulation methods. Here, by using molecular dynamics (MD) and MDeNM (Molecular Dynamics with excited Normal Modes) simulation methods, we present how rigid the C-terminal region is in the inactive RanGDP form and for the first time in the literature, we were able to follow its conformational flexibility in the GTP-bound form. This conformational mapping allows us to envisage how the C-terminus can embrace RanBDs during the function of Ran.

The simulations were carried out by JC, and were analyzed and interpreted by JC, PR, BD, HJ, RN, DP, and EB.