TRAPP Complexes in Secretion and Autophagy

Abstract

TRAPP is a highly conserved modular multi-subunit protein complex. Originally identified as a "transport protein particle" with a role in endoplasmic reticulum-to-Golgi transport, its multiple subunits and their conservation from yeast to humans were characterized in the late 1990s. TRAPP attracted attention when it was shown to act as a Ypt/Rab GTPase nucleotide exchanger, GEF, in the 2000s. Currently, three TRAPP complexes are known in yeast, I, II, and III, and they regulate two different intracellular trafficking pathways: secretion and autophagy. Core TRAPP contains four small subunits that self assemble to a stable complex, which has a GEF activity on Ypt1. Another small subunit, Trs20/Sedlin, is an adaptor required for the association of core TRAPP with larger subunits to form TRAPP II and TRAPP III. Whereas the molecular structure of the core TRAPP complex is resolved, the architecture of the larger TRAPP complexes, including their existence as dimers and multimers, is less clear. In addition to its Ypt/Rab GEF activity, and thereby an indirect role in vesicle tethering through Ypt/Rabs, a direct role for TRAPP as a vesicle tether has been suggested. This idea is based on TRAPP interactions with vesicle coat components. While much of the basic information about TRAPP complexes comes from yeast, mutations in TRAPP subunits were connected to human disease. In this review we will summarize new information about TRAPP complexes, highlight new insights about their function and discuss current controversies and future perspectives.

Keywords: GEF; GTPase; Rab; Ypt; autophagy; secretion; tether.

Figure 1

Yeast TRAPP complexes. (A) Core TRAPP, which contains four small subunits with two copies of Bet3 (3a and 3b), self assembles, binds Ypt1 through Bet5 and Trs23 and acts as a Ypt1-GEF. The diagram is based on the published structure of core TRAPP in a complex with Ypt1 (Cai et al., 2008). (B) TRAPP I contains core TRAPP, Trs20 and Trs33. However, it is not clear that the presence of the latter two subunits (in gray) is required for its function. The diagram is based on the published EM structure of core TRAPP subunits with Trs33 or Trs20 (Kim et al., 2006). (C) TRAPP III contains core TRAPP, Trs20 (orange), which is required for its assembly with Trs85 (green) and its function in autophagy. A role for Trs33 (in gray) in this complex has not been shown. The diagram is based on the published architecture and mutational analysis of TRAPP III (Tan et al., ; Taussig et al., 2014). (D) TRAPP II contains TRAPP I, including Trs20 (orange) and Trs33, and three large subunits: Trs120, Trs130, and the non-essential Trs65. Trs20 is required for the interaction of TRAPP I with Trs120, and either Trs65 or Trs33 are required for assembly of TRAPP II in vivo. TRAPP II is depicted here as a dimer (see discussion in the text). The cubes representing the subunits are roughly proportionate to their size; numbers stand for TrsN, except for Bet3 and Bet5. Approximate length (Å) is based on crystal structure for core TRAPP and negative staining EM for the other complexes (see text).

Figure 2

The role of TRAPP complexes and their Ypt substrates in yeast intra-cellular trafficking. In the exocytic pathway (top), TRAPP I activates Ypt1 to regulate ER-to-Golgi transport, whereas TRAPP II activates Ypt31/32 to regulate Golgi-to-PM transport. In autophagy (bottom), a cellular recycling pathway (in green), TRAPP III activates Ypt1 to regulate the assembly of PAS, the first step of autophagy. PAS is required for the formation of the double-membrane autophagosome (AP), which delivers cargo for degradation in the lysosome. See discussion in the text.