Dynamics of RASSF1A/MOAP-1 Association with Death Receptors

Franklin W. Olin College of Engineering, Olin Way, Needham, MA, USA 02492; Division of Experimental Oncology, Cross Cancer Institute, Edmonton, AB, Canada, T6G 1Z2; Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, T6G 2N8; Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673

^* To whom correspondence should be addressed. Email: sbaksh{at}ualberta.ca.

	Abstract

RASSF1A is a tumor suppressor protein involved in death receptor-dependent apoptosis utilizing the Bax-interacting protein, MOAP-1 (previously referred to as MAP-1). However, the dynamics of death receptor recruitment of RASSF1A and MOAP-1 are still not understood. We have now detailed recruitment to death receptors (TNF-R1 and TRAIL-R1/DR4), and identified domains of RASSF1A and MOAP-1 that are required for death receptor interaction. Upon TNF stimulation, the C-terminal region of MOAP-1 associated with the death domain of TNF-R1; subsequently, RASSF1A was recruited to MOAP-1/TNF-R1 complexes. Prior to recruitment to TNF-R1/MOAP-1 complexes, RASSF1A homodimerization was lost. RASSF1A associated with the TNF-R1/MOAP-1 or TRAIL-R1/MOAP-1 complex via its N-terminal cysteine-rich (C1) domain containing a potential zinc finger binding motif. Importantly, TNF-R1 association domains on both MOAP-1 and RASSF1A were essential for death receptor-dependent apoptosis. The association of RASSF1A and MOAP-1 with death receptors involves an ordered recruitment to receptor complexes to promote cell death and inhibit tumor formation.