Structural biology of DOCK‐family guanine nucleotide exchange factors

Abstract

Edited by Jacqueline Cherfils DOCK proteins are a family of multi-domain guanine nucleotide exchange factors (GEFs) that activate the RHO GTPases CDC42 and RAC1, thereby regulating several RHO GTPase-dependent cellular processes. DOCK proteins are characterized by the catalytic DHR2 domain (DOCK DHR2 ), and a phosphatidylinositol(3,4,5)P 3 -binding DHR1 domain (DOCK DHR1 ) that targets DOCK proteins to plasma membranes. DOCK-family GEFs are divided into four subfamilies (A to D) differing in their specificities for CDC42 and RAC1, and the composition of accessory signalling domains. Additionally, the DOCK-A and DOCK-B subfamilies are constitutively associated with ELMO proteins that auto-inhibit DOCK GEF activity. We review structural studies that have provided mechanistic insights into DOCK-protein functions. These studies revealed how a conserved nucleotide sensor in DOCK DHR2 catalyses nucleotide exchange, the basis for how different DOCK proteins activate specifically CDC42 and RAC1, and sometimes both, and how upstream regulators relieve the ELMO-mediated auto-inhibition. We conclude by presenting a model for full-length DOCK9 of the DOCK-D subfamily. The involvement of DOCK GEFs in a range of diseases highlights the importance of gaining structural insights into these proteins to better understand and specifically target them.

Molecular principles of bidirectional signalling between membranes and small GTPases

“…As an example, we used this framework to examine the contribution of membranes to the activation of Rac GTPases by their GEFs of the DOCK (dedicator of cytokinesis) family, using landmark cryo‐EM structures of unbound and Rac‐bound DOCK that have been published recently ([62,63], reviewed in ref. [64]) (Fig. 1B).…”

“…The ELMO‐DOCK2 and ELMO‐DOCK5 complexes bound to Rac1 have a similar organization ([62,63], reviewed in ref. [64]) (Fig. 5A).…”

“…Crystal structures of RhoG‐GTP bound to the N‐terminal domain of ELMO1 [62], and of a BAI1 peptide bound to the armadillo repeats of ELMO2 [71] show that the binding sites of both regulators are available only in the active, Rac1‐bound ELMO/DOCK configuration (reviewed in ref. [64]) (Fig. 5E).…”

“…A surprising discovery from the cryo-EM structures of Rac-bound DOCK/ELMO complexes is that the DHR1 domains and Rac1 Ct dimers are located at different distances from the membrane ( [62,63], reviewed in ref. [64]), which we extend here to include ELMO PH . The DHR1 domains tower the DHR2 domains by about 40 A, such that symmetrical binding of the two DHR1 domains to phospholipids would position the DHR2 active sites away from the membrane by the same distance.…”

Small GTPase signaling hubs at the surface of cellular membranes in physiology and disease

“…These reviews highlight the critical role of membranes in enforcing the specificities of each TRAPP complex towards a particular set of Rab GTPases, through the combination of specific regulatory subunits, recognition of distinct features of particular Rabs in the context of membranes, and conformational rearrangements. Barford and co-workers present how structural information on dedicator of cytokinesis (DOCK) proteins, which are dimeric GEFs for Rac family GTPases, shed light on their activation mechanism and their regulation by engulfment and cell motility and the small GTPase RhoG in cytoskeletal dynamics [10]. Arf GTPases, which are major regulators of most aspects of cellular traffic, form a more remote subfamily (to which Sar GTPases and possibly the Rag GTPases and bacterial mutual gliding-motility protein A [MglA] are related), characterized by a unique allosteric mechanism whereby the nucleotide-binding site communicates with the membrane [14].…”