GTPase Networks in Membrane Traffic

Abstract

Members of the Rab or ARF/Sar branches of the Ras GTPase super-family regulate almost every step of intracellular membrane traffic. A rapidly growing body of evidence indicates that these GTPases do not act as lone agents but are networked to one another through a variety of mechanisms to coordinate the individual events of one stage of transport and to link together the different stages of an entire transport pathway. These mechanisms include guanine nucleotide exchange factor (GEF) cascades, GTPase-activating protein (GAP) cascades, effectors that bind to multiple GTPases, and positive-feedback loops generated by exchange factor-effector interactions. Together these mechanisms can lead to an ordered series of transitions from one GTPase to the next. As each GTPase recruits a unique set of effectors, these transitions help to define changes in the functionality of the membrane compartments with which they are associated.

Rab6a releases LIS1 from a dynein idling complex and activates dynein for retrograde movement

“…Among them, other Rabs may be present for activation of dynein in a similar fashion. Rab proteins are further regulated by a diverse group of structurally unrelated GDP-GTP exchange factors and a family of GTP-hydrolysis-activating proteins 40,41 . For example, various DENN domains interact directly with members of the Rab family of small GTPases, and DENN (differentially expressed in normal and neoplastic cells) domains function enzymatically as Rab-specific guanine nucleotide exchange factors 42,43 .…”

ENDOSOMAL RAB EFFECTOR WITH PX-DOMAIN, an Interacting Partner of RAB5 GTPases, Regulates Membrane Trafficking to Protein Storage Vacuoles in Arabidopsis

“…When RAB GTPases are activated by the replacement of GDP with GTP, which is mediated by guanine nucleotide exchange factors (GEFs), they interact with specific sets of interacting partners collectively called RAB effectors. Through their interaction with effector molecules, RAB GTPases evoke a wide spectrum of downstream events, including the tethering of transport vesicles to target organelles, the formation of subdomains on organelle membranes, organelle movement, alteration of lipid composition in organelle membranes, and organelle maturation (Stenmark, 2009;Mizuno-Yamasaki et al, 2012). Once GTP is hydrolyzed by the action of GTPase activating proteins, the GDP-bound RAB proteins are detached from the membranes by forming complexes with GDP dissociation inhibitors and are retained in the cytosol until the next round of the GTPase cycle (Seabra and Wasmeier, 2004;Goody et al, 2005).…”

Expanding Proteostasis by Membrane Trafficking Networks

“…Moreover, the CTF system forms dynamic complexes that control the temporal and spatial features of endomembrane architecture and function through the information encoded by the primary polypeptide sequence, but presented in the context of the fold (the secondary, tertiary, and quaternary structural features) of each cargo (Nishimura et al 1999;Miller and Barlowe 2010;Kelly and Owen 2011). The dynamic properties of CTF biology are illustrated by (1) the collapse of the Golgi into the ER in response to brefeldin A-mediated inhibition of COPI coat assembly; (2) the role of diverse cargo in managing CTF-based compartment identity (Springer and Schekman 1998;Aridor et al 1999;Mettlen et al 2010); (3) the role of small GTPases in regulating the trajectories of CTF complexes (Hutagalung and Novick 2011;Mizuno-Yamasaki et al 2012); and (4) the sensitivity of compartment architecture to diverse physiologically and environmentally triggered signaling pathways.…”

“…3B) (Hutt et al 2009;Powers et al 2009). However, and unique to the TPN compared with the PN, is the central role of GTPases to manage the construction of quinary folding environments by regulating sequential TRaCKS assembly and disassembly (Allan et al 2000;Hutagalung and Novick 2011;Lord et al 2011;Mizuno-Yamasaki et al 2012). This "directed maturation" (Allan and Balch 1999) reflects the need for global integration of TPN biology through the activity of cargo-based TRaCKS (Springer and Schekman 1998;Aridor et al 1999;Mettlen et al 2010).…”

“…Misfolded proteins are a major concern of proteostasis biology (Broadley and Hartl 2009;Powers et al 2009;Douglas and Cyr 2010;Taipale et al 2010;Voisine et al 2010;Ong and Kelly 2011) and a key concern for TPN biology (Saksena and Emr 2009;Miller and Barlowe 2010;Routledge et al 2010;Roth and Balch 2011;Mizuno-Yamasaki et al 2012;Zanetti et al 2012). In addition to the more than 7000 rare misfolding disorders defective in folding and trafficking responsible for disease, their are numerous examples of mutations in the CTF TPN components that affect trafficking and contribute to a diversity of inherited diseases.…”