Novel type of Ras effector interaction established between tumour suppressor NORE1A and Ras switch II.
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.
Stieglitz
Benjamin
B
Physikalische Chemie 1, Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Bochum, Germany.
Bee
Christine
C
Schwarz
Daniel
D
Yildiz
Ozkan
O
Moshnikova
Anna
A
Khokhlatchev
Andrei
A
Herrmann
Christian
C
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016296:Mutagenesis; D054730:Protein Interaction Domains and Motifs; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C411762:RASSF1 protein, human; C454042:RASSF5 protein, human; C455831:Rassf5 protein, mouse; D025521:Tumor Suppressor Proteins; D020559:Monomeric GTP-Binding Proteins; D018631:ras Proteins