BAG4/SODD Protein Contains a Short BAG Domain

Klára Briknarová,Shinichi Takayama,Sachiko Homma,Kelly Baker,Edelmira Cabezas,David W Hoyt,Zhen Li,Arnold C Satterthwait,Kathryn R Ely

doi:10.1074/jbc.m202792200

Abstract

BAG (Bcl-2-associated athanogene) proteins are molecular chaperone regulators that affect diverse cellular pathways. All members share a conserved motif, called the BAG domain (BD), which binds to Hsp70/Hsc70 family proteins and modulates their activity. We have determined the solution structure of BD from BAG4/SODD (silencer of death domains) by multidimensional nuclear magnetic resonance methods and compared it to the corresponding domain in BAG1 (Briknarová, K., Takayama, S., Brive, L., Havert, M. L., Knee, D. A., Velasco, J., Homma, S., Cabezas, E., Stuart, J., Hoyt, D. W., Satterthwait, A. C., Llinás, M., Reed, J. C., and Ely, K. R. (2001) Nat. Struct. Biol. 8, 349-352). The difference between BDs from these two BAG proteins is striking, and the structural comparison defines two subfamilies of mammalian BD-containing proteins. One subfamily includes the closely related BAG3, BAG4, and BAG5 proteins, and the other is represented by BAG1, which contains a structurally and evolutionarily distinct BD. BDs from both BAG1 and BAG4 are three-helix bundles; however, in BAG4, each helix in this bundle is three to four turns shorter than its counterpart in BAG1, which reduces the length of the domain by one-third. BAG4 BD thus represents a prototype of the minimal functional fragment that is capable of binding to Hsc70 and modulating its chaperone activity.

Highlights

From ‡The Burnham Institute, La Jolla, California 92037 and §Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington 99352
One subfamily includes the closely related BAG3, BAG4, and BAG5 proteins, and the other is represented by BAG1, which contains a structurally and evolutionarily distinct BAG domain (BD)
BAG4 (SODD), on the other hand, may play a role as a cellular “adaptor.” It has been speculated that BAG4 recruits Hsc70 to tumor necrosis factor receptor 1 (TNFR1) and death receptor 3 (DR3) [2, 7], inducing conformational changes that prevent receptor signaling in the absence of ligand

Summary

Introduction

From ‡The Burnham Institute, La Jolla, California 92037 and §Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington 99352. BAG4/SODD Protein Contains a Short BAG Domain* All members share a conserved motif, called the BAG domain (BD), which binds to Hsp70/Hsc70 family proteins and modulates their activity.

Results

Conclusion