Longins and their longin domains: regulated SNAREs and multifunctional SNARE regulators

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Longins are the only R-SNAREs that are common to all eukaryotes and are characterized by a conserved N-terminal domain with a profilin-like fold called a longin domain (LD). These domains seem to be essential for regulating membrane trafficking and they mediate unexpected biochemical functions via a range of protein–protein and intramolecular binding specificities. In addition to the longins, proteins involved in the regulation of intracellular trafficking, such as subunits of the adaptor and transport protein particle complexes, also have LD-like folds. The functions and cellular localization of longins are regulated at several levels and the longin prototypes TI-VAMP, Sec22 and Ykt6 show different distributions among eukaryotes, reflecting their modular and functional diversity. In mammals, TI-VAMP and Ykt6 are crucial for neuronal function, and defects in longin structure or function might underlie some human neurological pathologies.

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Molecular organization and functions of LDs

Figure 1 compares the domain architecture of longins to that of other SNAREs. Both longins and syntaxins have N-terminal domains (NTDs) that can downregulate membrane fusion 15, 16, 17. When the 3D structures of the NTDs of the longins Ykt6 and Sec22b were solved, however, the LD was found to show a conserved profilin-like fold that differed considerably from that of the NTD of syntaxins 18, 19 (Box 1).

Intramolecular binding of the NTD of neuronal syntaxin to its SNARE motif mediates the

TI-VAMP

Depending on the type of cell, TI-VAMP has been found to interact in vivo with several t-SNARE heavy chains (plasmalemmal syntaxin 1, 3 and 4, and late endosomal syntaxin 7) and light chains (SNAP-23, -25 and -29, syntaxins 6, 8 and 10, and Vti1b), but not with syntaxin 16 (in the Golgi) or syntaxin 13 (in early endosomes) 11, 17, 22, 29, 33, 34, 35, 36. Although physiological roles for all of these associations remain to be determined, these interactions clearly indicate that TI-VAMP is

Sec22 and Ykt6

The proteome of yeast Saccharomyces cerevisiae contains five R-SNAREs: its two ‘brevins’ 7, 8 (Snc1 and Snc2) function in trafficking to the cell surface, both within the endosomal system and between endosomes and the Golgi [50]; Nyv1 is the largest of the five R-SNAREs and the least similar to the other four [51]; and the two longins (Sec22 and Ykt6) are evolutionarily conserved proteins, but only Ykt6 is essential [14].

Distribution and domain variation

Although longins represent the most conserved and widely distributed R-SNAREs in terms of both their LDs and their SNARE motifs 7, 10, a comparison of the R-SNARE proteomic complements from model eukaryotes with completely sequenced genomes demonstrates that the longin subfamilies show different distributions and varying numbers of members among taxa (Table 1).

The Sec22 and Ykt6 longins have an apparently homogeneous distribution and number of genes, whereas the TI-VAMP longins and brevins are

Concluding remarks

The SNARE family has remained mostly unchanged in yeast, flies and worms, but has significantly increased in the number of representatives in mammals [6] and plants [9]. These features suggest that multicellular organisms, first, do not have an inherently more complex secretory pathway and, second, use additional SNAREs for the tissue-specific specialization of membrane trafficking [6]. The possibility that longins and brevins might have different roles in differentiation, development and

Acknowledgements

This manuscript is dedicated to the memory of Giuliana Ferrarone. V.R. and M.V. are supported, respectively, by a research associate and a postdoctoral fellowship funded by the University of Padua. L.E.P.D. is a recipient of a predoctoral fellowship of the Boehringer Ingelheim Fonds. D.K.B.'s laboratory is supported by the Research Grants Council of Hong Kong; C.U.'s laboratory by the DFG, the SFB638, the Fonds der Chemischen Industrie and the EMBO young investigator programme; M.D.E.'s

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