Article
- The EMBO Journal (2008) 27, 1995 - 2005
- doi:10.1038/emboj.2008.125
Published online: 3 July 2008
Subject Categories:
Novel type of Ras effector interaction established between tumour suppressor NORE1A and Ras switch II
Benjamin Stieglitz1,a, Christine Bee1, Daniel Schwarz1, Özkan Yildiz2, Anna Moshnikova3, Andrei Khokhlatchev3 and Christian Herrmann1
- Physikalische Chemie 1, Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Bochum, Germany
- Max-Planck-Institut für Biophysik, Abteilung Strukturelle Biologie, Frankfurt, Germany
- Department of Pathology, University of Virginia Health Science Center, Charlottesville, VA, USA
Correspondence to:
Christian Herrmann, Physikalische Chemie I, Ruhr-Universität Bochum, Arbeitsgruppe Protein-Interaktionen, Fakultät für Chemie, Universitätsstrasse 150, 44780 Bochum, Germany. Tel.: +49 0234 322 4173; Fax: +49 0234 321 4785; E-mail: chr.herrmann@rub.de
aPresent address: MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
Received 5 March 2008; Accepted 4 June 2008
Abstract
A class of putative Ras effectors called Ras association domain family (RASSF) represents non-enzymatic adaptors that were shown to be important in tumour suppression. RASSF5, a member of this family, exists in two splice variants known as NORE1A and RAPL. Both of them are involved in distinct cellular pathways triggered by Ras and Rap, respectively. Here we describe the crystal structure of Ras in complex with the Ras binding domain (RBD) of NORE1A/RAPL. All Ras effectors share a common topology in their RBD creating an interface with the switch I region of Ras, whereas NORE1A/RAPL RBD reveals additional structural elements forming a unique Ras switch II binding site. Consequently, the contact area of NORE1A is extended as compared with other Ras effectors. We demonstrate that the enlarged interface provides a rationale for an exceptionally long lifetime of the complex. This is a specific attribute characterizing the effector function of NORE1A/RAPL as adaptors, in contrast to classical enzymatic effectors such as Raf, RalGDS or PI3K, which are known to form highly dynamic short-lived complexes with Ras.
Keywords:
- adaptor,
- apoptosis,
- interface,
- lifetime,
- protein interaction
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