The TRAPP complexes: oligomeric exchange factors that activate the small GTPases Rab1 and Rab11

Abstract

The Transport Protein Particle (TRAPP) complexes are highly conserved multisubunit complexes that act as nucleotide exchange factors (GEFs) for Rab GTPases. They act in both protein secretion and autophagy and have also been proposed to have a role in other processes such as cytokinesis and ciliogenesis. There are two TRAPP complexes in metazoans: TRAPPII, which activates Rab11; and TRAPPIII, which activates Rab1. Both complexes share a core of small subunits that form the active site for the exchange of GDP for GTP. In addition, each TRAPP complex has distinct large subunits that determine the specificity of each complex towards its substrate Rab and are essential for activity in vivo. Crystal structures have revealed the organisation of the TRAPP core and the mechanism of Rab1 activation, whilst recent cryo‐EM structures have unveiled the arrangement of the specific subunits around the core to form each complex. Combining these findings with functional experiments has allowed the proposal of mechanisms for how the specificity of each complex towards their cognate Rab is determined and for the arrangement of these large complexes on the membrane.

Microcephaly with a disproportionate hippocampal reduction, stem cell loss and neuronal lipid droplet symptoms inTrappc9KO mice

“…Trappc9 forms a subunit of the metazoan TrappII multi-protein complex, which regulates vesicle trafficking, endosome recycling and lipid droplet homeostasis (Galindo & Munro, 2023; Li et al, 2017). TrappII and the related TrappIII complex share seven core subunits, but are distinguished by the association of specific subunits, i.e.…”

“…TrappII and the related TrappIII complex share seven core subunits, but are distinguished by the association of specific subunits, i.e. Trappc9 and Trappc10 in TrappII and Trappc8, c11, c12 and c13 in TrappIII (Galindo & Munro, 2023). Recent structural analyses of the TrappII complex revealed a triangular shape with the large c9 and c10 subunits forming two sides of the triangle (Galindo & Munro, 2023; Jenkins et al, 2020).…”

“…Trappc9 and Trappc10 in TrappII and Trappc8, c11, c12 and c13 in TrappIII (Galindo & Munro, 2023). Recent structural analyses of the TrappII complex revealed a triangular shape with the large c9 and c10 subunits forming two sides of the triangle (Galindo & Munro, 2023; Jenkins et al, 2020). The complexes attach to intracellular membranes via binding to specific membrane-anchored Rab proteins, for which they have an activating guanine nucleotide exchange factor (GEF) function.…”

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

“…GEFs are generally multidomain proteins with conformational plasticity and often assemble in multisubunit complexes that interact with membranes to activate small GTPases attached to membranes. Galindo and Munro [6] and Bagde and Fromme [5] discuss how combined crystallography, cryo-electron microscopy, and in vitro reconstitutions uncovered major features of the architecture, mechanism, and specificity of the yeast and metazoan transport protein particle (TRAPP)II and TRAPIII complexes, two related multisubunit GEFs for Rab GTPases, which function in secretion and autophagy. 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.…”

“…We are now delighted to present 13 articles that highlight how integrated structural, biochemical, and biophysical approaches have allowed to shed light on the mechanisms of fundamental functions of major members of this superfamily. Notably, these reviews show how several experimental approaches that were rarely used a decade ago, are now taking center stage in moving the field forward: reconstitutions of small GTPase systems in artificial membranes [5][6][7][8][9], single particle cryo-electron microscopy [5][6][7][9][10][11][12], 3D electron tomography reconstructions [12], or optogenetics [13]. Of these, Loose and coauthors present a great overview of the power and inherent difficulties of in vitro reconstitutions using biomimetic membranes, and how they have revealed in a quantitative manner the inner workings of intricate small GTPase networks, which would have been unattainable in vivo [8].…”