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Molecular and Cellular Biology, April 2002, p. 2536-2543, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2536-2543.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Tumor Necrosis Factor Receptor 1 Is an ATPase Regulated by Silencer of Death Domain

Kiyoshi Miki and Edward M. Eddy*

Gamete Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709

Received 26 November 2001/ Accepted 29 January 2002

Self-aggregation of tumor necrosis factor receptor type 1 (TNFR1) induces spontaneous downstream signaling and results in cell death. It has been suggested that silencer of death domain (SODD) binds TNFR1 monomers to prevent self-aggregation. We found that SODD binds through its BAG domain to the ATPase domain of Hsp70. We also determined that SODD binds through its BAG domain to TNFR1. ATP, but not nonhydrolyzable ATP-{gamma}S, regulates the SODD binding by Hsp70 or TNFR1. ATP binding by TNFR1 was abolished when a point mutation was introduced into a phosphate-binding loop motif characteristic of ATP-binding proteins, suggesting that TNFR1 functions as an ATPase. Furthermore, TNFR1 was present in aggregates in ATP-depleted cells and SODD disassembled aggregates in vitro only in the presence of ATP. These data suggest that SODD functions as a cofactor analogous to the nucleotide exchange factor BAG-1, which modulates the ATPase cycle of Hsp70 proteins. We propose a new model in which a nucleotide-dependent conformational change in TNFR1 has a key role in regulating TNF signaling.

* Corresponding author. Mailing address: LRDT, MD C4-01, NIEHS, NIH, 111 T.W. Alexander Dr., Research Triangle Park, NC 27709. Phone: (919) 541-3015. Fax: (919) 541-3800. E-mail: eddy{at}niehs.nih.gov.

Molecular and Cellular Biology, April 2002, p. 2536-2543, Vol. 22, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.8.2536-2543.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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