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Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2012 Feb 28; Vol. 109 (9), pp. 3305-10. Date of Electronic Publication: 2012 Feb 13. - Publication Year :
- 2012
-
Abstract
- DOCK2, a hematopoietic cell-specific, atypical guanine nucleotide exchange factor, controls lymphocyte migration through ras-related C3 botulinum toxin substrate (Rac) activation. Dedicator of cytokinesis 2-engulfment and cell motility protein 1 (DOCK2•ELMO1) complex formation is required for DOCK2-mediated Rac signaling. In this study, we identified the N-terminal 177-residue fragment and the C-terminal 196-residue fragment of human DOCK2 and ELMO1, respectively, as the mutual binding regions, and solved the crystal structure of their complex at 2.1-Å resolution. The C-terminal Pro-rich tail of ELMO1 winds around the Src-homology 3 domain of DOCK2, and an intermolecular five-helix bundle is formed. Overall, the entire regions of both DOCK2 and ELMO1 assemble to create a rigid structure, which is required for the DOCK2•ELMO1 binding, as revealed by mutagenesis. Intriguingly, the DOCK2•ELMO1 interface hydrophobically buries a residue which, when mutated, reportedly relieves DOCK180 from autoinhibition. We demonstrated that the ELMO-interacting region and the DOCK-homology region 2 guanine nucleotide exchange factor domain of DOCK2 associate with each other for the autoinhibition, and that the assembly with ELMO1 weakens the interaction, relieving DOCK2 from the autoinhibition. The interactions between the N- and C-terminal regions of ELMO1 reportedly cause its autoinhibition, and binding with a DOCK protein relieves the autoinhibition for ras homolog gene family, member G binding and membrane localization. In fact, the DOCK2•ELMO1 interface also buries the ELMO1 residues required for the autoinhibition within the hydrophobic core of the helix bundle. Therefore, the present complex structure reveals the structural basis by which DOCK2 and ELMO1 mutually relieve their autoinhibition for the activation of Rac1 for lymphocyte chemotaxis.
- Subjects :
- Adaptor Proteins, Signal Transducing chemistry
Amino Acid Sequence
Crystallography, X-Ray
GTPase-Activating Proteins
Guanine Nucleotide Exchange Factors chemistry
Humans
Hydrophobic and Hydrophilic Interactions
Models, Molecular
Molecular Sequence Data
Nuclear Magnetic Resonance, Biomolecular
Protein Binding
Protein Conformation
Protein Interaction Mapping
Protein Structure, Secondary
Recombinant Fusion Proteins chemistry
Recombinant Fusion Proteins metabolism
Sequence Alignment
Sequence Homology, Amino Acid
rac1 GTP-Binding Protein chemistry
rac1 GTP-Binding Protein metabolism
src Homology Domains
Adaptor Proteins, Signal Transducing metabolism
Guanine Nucleotide Exchange Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 109
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 22331897
- Full Text :
- https://doi.org/10.1073/pnas.1113512109