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6aj4

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Crystal structure of the DHR-2 domain of DOCK7 in complex with Cdc42

Structural highlights

6aj4 is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.256Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DOCK7_HUMAN Early-onset epileptic encephalopathy-cortical blindness-intellectual disability-facial dysmorphism syndrome. The disease is caused by mutations affecting the gene represented in this entry.

Function

DOCK7_HUMAN Functions as a guanine nucleotide exchange factor (GEF), which activates Rac1 and Rac3 Rho small GTPases by exchanging bound GDP for free GTP. Does not have a GEF activity for CDC42. Required for STMN1 'Ser-15' phosphorylation during axon formation and consequently for neuronal polarization (PubMed:16982419). Has a role in pigmentation (By similarity). Involved in the regulation of cortical neurogenesis through the control of radial glial cells (RGCs) proliferation versus differentiation; negatively regulates the basal-to-apical interkinetic nuclear migration of RGCs by antagonizing the microtubule growth-promoting function of TACC3 (By similarity).[UniProtKB:Q8R1A4]^[1]

Publication Abstract from PubMed

The Dedicator Of CytoKinesis (DOCK) family of atypical guanine nucleotide exchange factors activates the Rho family GTPases Rac and/or Cdc42 through DOCK homology region 2 (DHR-2). Previous structural analyses of the DHR-2 domains of DOCK2 and DOCK9 have shown that they preferentially bind Rac1 and Cdc42, respectively; however, the molecular mechanism by which DHR-2 distinguishes between these GTPases is unclear. Here we report the crystal structure of the Cdc42-bound form of the DOCK7 DHR-2 domain showing dual specificity for Rac1 and Cdc42. The structure revealed increased substrate tolerance of DOCK7 at the interfaces with switch 1 and residue 56 of Cdc42. Furthermore, molecular dynamics simulations showed a closed-to-open conformational change in the DOCK7 DHR-2 domain between the Cdc42- and Rac1-bound states by lobe B displacement. Our results suggest that lobe B acts as a sensor for identifying different switch 1 conformations and explain how DOCK7 recognizes both Rac1 and Cdc42.

Structural Basis for the Dual Substrate Specificity of DOCK7 Guanine Nucleotide Exchange Factor.,Kukimoto-Niino M, Tsuda K, Ihara K, Mishima-Tsumagari C, Honda K, Ohsawa N, Shirouzu M Structure. 2019 Feb 16. pii: S0969-2126(19)30045-0. doi:, 10.1016/j.str.2019.02.001. PMID:30853411^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Watabe-Uchida M, John KA, Janas JA, Newey SE, Van Aelst L. The Rac activator DOCK7 regulates neuronal polarity through local phosphorylation of stathmin/Op18. Neuron. 2006 Sep 21;51(6):727-39. PMID:16982419 doi:http://dx.doi.org/S0896-6273(06)00585-X
↑ Kukimoto-Niino M, Tsuda K, Ihara K, Mishima-Tsumagari C, Honda K, Ohsawa N, Shirouzu M. Structural Basis for the Dual Substrate Specificity of DOCK7 Guanine Nucleotide Exchange Factor. Structure. 2019 Feb 16. pii: S0969-2126(19)30045-0. doi:, 10.1016/j.str.2019.02.001. PMID:30853411 doi:http://dx.doi.org/10.1016/j.str.2019.02.001