Invisible leashes: The tethering VAPs from infectious diseases to neurodegeneration

Abstract

Intracellular organelles do not, as thought for a long time, act in isolation but are dynamically tethered together by entire machines responsible for interorganelle trafficking and positioning. Among the proteins responsible for tethering is the family of VAMP-associated proteins (VAPs) that appear in all eukaryotes and are localized primarily in the endoplasmic reticulum. The major functional role of VAPs is to tether the endoplasmic reticulum with different organelles and regulate lipid metabolism and transport. VAPs have gained increasing attention because of their role in human pathology where they contribute to infections by viruses and bacteria and participate in neurodegeneration. In this review, we discuss the structure, evolution, and functions of VAPs, focusing more specifically on VAP-B for its relationship with amyotrophic lateral sclerosis and other neurodegenerative diseases.

Keywords: ALS; VAMP; endoplasmic reticulum; tethering proteins.

Figure 1

The structure of VAPs.A, schematic representation of the domain architecture along the sequence. B, three-dimensional structure of VAP-B (PDB code: 3ikk) as a stereo view. The two prolines indicated (P12 and P56) are the points at which the strands switch from one sheet to the other as described in section “The peculiarities of the Ig-fold of the MSP family.” The region shown in orange (residues 42–57) shows the VAP consensus sequence. PDB, Protein Data Bank.

Figure 2

Similarities and differences within the Ig superfamily.A, schematic representation of the Ig C-, V-, I- and S-fold types. The two distinct sheets of the β-sandwich are indicated in blue and purple. B, comparison in stereo of the three-dimensional structures of VAP-B (PDB code: 3ikk), MSP (PDB code: 1grw), and PapD (PDB code: 3dpa). Ig, immunoglobulin; PDB, Protein Data Bank.

Figure 3

Schematic overview of the evolution of proteins containing the VAP domain based on sequence analysis, with emphasis on the three domain architectures observed in the metazoa. Homology with the prokaryotic PapD cannot be established and is indicated with a question mark. The VAP-A architecture with the MSP domain, a coiled-coil, and a transmembrane helix can be found throughout eukaryotes and therefore probably dates back to the last eukaryotic common ancestor (LECA). Many variations on this architecture can be found, including the loss of the coiled-coil region or the C-terminal transmembrane helix. There are also several gene duplications in the family in the various taxa, such as in plants. Species for which structures have been determined are named in figure. MSP, major sperm protein.

Figure 4

VAP-B tether between the ER and mitochondria and its link to neurodegeneration. VAP-B and PTPIP51 are normally linked together with interactions between VAP-B and a complementary region of PTPIP51. TDP-43 and fused in sarcoma/translocated in liposarcoma protein may activate GSK3β that, in turn, inhibits binding of VAP-B to PTPIP51 and reduce the ER–mitochondria connections. This is thought to cause dysregulation and disease. ER, endoplasmic reticulum.

Figure 5

Mapping ALS-related mutations onto the structure of the MSP domain of VAP-B (PDB code: 3ikk). The backbone of the protein is shown as a ribbon in stereo. The adopted view differs from that of Figure 1 by a rotation of 90 degrees around an axis on the page. The side chains of T46 and P56 are shown. T46 has an accessible surface area of 31 Å² and is thus semiexposed. P56 is also semiexposed (48 Å²) and is key in defining the switching point of strand C’. ALS, amyotrophic lateral sclerosis; MSP, major sperm protein; PDB, Protein Data Bank.

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