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Molecular and Cellular Biology, July 2000, p. 4870-4878, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Isoform-Specific Localization of A-RAF in Mitochondria

Anton Yuryev,1,dagger Makoto Ono,2 Stephen A. Goff,2,Dagger Frank Macaluso,3 and Lawrence P. Wennogle1,*

Novartis Institute for Biomolecular Research, Summit, New Jersey1; Novartis Agricultural Biotechnology Research Unit, Research Triangle Park, North Carolina2; and Albert Einstein College of Medicine, Bronx, New York3

Received 4 November 1999/Returned for modification 10 January 2000/Accepted 13 March 2000

RAF kinase is a family of isoforms including A-RAF, B-RAF, and C-RAF. Despite the important role of RAF in cell growth and proliferation, little evidence exists for isoform-specific function of RAF family members. Using Western analysis and immunogold labeling, A-RAF was selectively localized in highly purified rat liver mitochondria. Two novel human proteins, which interact specifically with A-RAF, were identified, and the full-length sequences are reported. These proteins, referred to as hTOM and hTIM, are similar to components of mitochondrial outer and inner membrane protein-import receptors from lower organisms, implicating their involvement in the mitochondrial transport of A-RAF. hTOM contains multiple tetratricopeptide repeat (TPR) domains, which function in protein-protein interactions. TPR domains are frequently present in proteins involved in cellular transport systems. In contrast, protein 14-3-3, an abundant cytosolic protein that participates in many facets of signal transduction, was found to interact with C-RAF but not with A-RAF N-terminal domain. This information is discussed in view of the important role of mitochondria in cellular functions involving energy balance, proliferation, and apoptosis and the potential role of A-RAF in regulating these systems.

* Corresponding author. Mailing address: Novartis Institute for Biomedical Research, 556 Morris Ave., LSB3165, Summit, NJ 07901. Phone: (908) 277-5697. Fax: (908) 277-4756. E-mail: lawrence.wennogle{at}pharma.novartis.com.

dagger Present address: InforMax Inc., North Bethesda, MD 20852.

Dagger Present address: NADDI, Scripps Institute, La Jolla, CA 92037.

Molecular and Cellular Biology, July 2000, p. 4870-4878, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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