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Structure and mutagenesis of the Dbl homology domain

Nature Structural Biology volume 5, pages 1098–1107 (1998)Cite this article

Abstract

Guanine nucleotide exchange factors in the Dbl family activate Rho GTPases by accelerating dissociation of bound GDP, promoting acquisition of the GTP-bound state. Dbl proteins possess a ∼200 residue catalytic Dbl-homology (DH) domain, that is arranged in tandem with a C-terminal pleckstrin homology (PH) domain in nearly all cases. Here we report the solution structure of the DH domain of human PAK-interacting exchange protein (βPIX). The domain is composed of 11 α-helices that form a flattened, elongated bundle. The structure explains a large body of mutagenesis data, which, along with sequence comparisons, identify the GTPase interaction site as a surface formed by three conserved helices near the center of one face of the domain. Proximity of the site to the DH C-terminus suggests a means by which PH-ligand interactions may be coupled to DH-GTPase interactions to regulate signaling through the Dbl proteins in vivo.

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Figure 1: Structure-based amino acid sequence alignment (manually modified Clustal) of selected Dbl homology domains.
Figure 2
Figure 3: Stereo view of the backbone (N, Cα, C') of 20 final superimposed structures of the βPIX DH domain.
Figure 4: a, Ribbons80 depiction of a representative conformer from the final ensemble of DH domain structures.
Figure 6: a, Molecular surface of the DH domain oriented as in Fig. 3.
Figure 5: a, Effect of Ser 1216 (corresponding to Thr 104 in βPIX) mutations on UNC-73 DH activity towards mammalian Rac GTPase.

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Acknowledgements

We thank Y. Min Chook and J. Goldberg for discussion and critical reading of the manuscript; J.Goldberg and S. Bagrodia and R. Cerione for communicating results prior to publication; L. Kay for generously providing many of the NMR pulse sequences used in this study; M. Clore for advice; A. Majumdar and Y. Gosser for assistance with NMR data acquisition; J. Hubbard for computer system support and S. Freihaut for expert administrative assistance. B.A. is supported by a grant from the U.S. Army Breast Cancer Program. M.K.R. gratefully acknowledges support from the National Institutes of Health (PECASE program), Arnold and Mabel Beckman Foundation and Sidney Kimmel Foundation for Cancer Research.

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Authors and Affiliations

  1. Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Behzad Aghazadeh, Grace A. Liu & Michael K. Rosen

  2. Graduate Program in Physiology and Biophysics, Cornell University Graduate School of Medical Sciences, New York, 10021, New York, USA

    Behzad Aghazadeh

  3. Graduate Program in Biochemistry and Structural Biology, Cornell University Graduate School of Medical Sciences, New York, 10021, New York, USA

    Michael K. Rosen

  4. Department of Biochemistry, University of Tennessee, Memphis, 38163, Tennessee, USA

    Kejin Zhu & Yi Zheng

  5. Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Ontario, Canada

    Terrance J. Kubiseski & Tony Pawson

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Aghazadeh, B., Zhu, K., Kubiseski, T. et al. Structure and mutagenesis of the Dbl homology domain. Nat Struct Mol Biol 5, 1098–1107 (1998). https://doi.org/10.1038/4209

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