Dock2 was first characterised as one of a number of proteins which shared high sequence similarity with the previously described protein Dock180, the archetypal member of the DOCK family. Whereas Dock180 expression is near ubiquitous in mammals, Dock2 appears to be expressed specifically in leukocytes and is considered to be the principal DOCK family member in these cells.
Dock2 is part of a large class of proteins (GEFs) which contribute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound to Guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate (GTP). GEFs activate G proteins by promoting this nucleotide exchange.
Dock2 and other DOCK family proteins differ from other GEFs in that they do not possess the canonical structure of tandem DH-PH domains known to elicit nucleotide exchange. Instead they possess a DHR2 domain which mediates Rac activation by stabilising it in its nucleotide-free state. They also contain a DHR1 domain which binds phospholipids and is required for the interaction between Dock2 and the plasma membrane. As with other members of the DOCK-A and DOCK-B subfamilies, Dock2 contains an N-terminalSH3 domain which is involved in binding to ELMO proteins (see below). Dock180 contains a C-terminalproline rich region which mediates binding to Crk, however, Dock2 lacks this feature despite the fact that it is able to bind the Crk-like protein CrkL.
Efficient Dock180 GEF activity in a cellular context is known to require the formation of a complex between Dock180 and its cognate adaptor proteins, which assist its translocation to the plasma mambrane and binding to Rac. Similarly, Dock2 has been shown to form a complex with the well described DOCK-binding protein ELMO1 and this interaction is required for Dock2-mediated Rac activation in lymphocyte cell lines. ELMO proteins contain a C-terminal proline-rich region which binds to the N-terminal SH3 domain of DOCK proteins and mediates their recruitment to sites of high Rac availability (primarily the plasma membrane). ELMO proteins also contain a PH domain which appears to induce conformational changes in DOCK and thus allow binding to Rac.
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