VASt domain
Identifiers
SymbolVASt domain
PfamPF16016
InterProIPR031968
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

VAD1 analog of StAR-related lipid transfer (VASt) is a steroidogenic acute regulatory protein‐related lipid transfer (StART)-like lipid-binding domain first identified in the vad1 (vascular associated death1) protein in Arabidopsis thaliana (mouse-ear cress ).[1][2] Proteins containing these domains are found in eukaryotes and usually contain another lipid-binding domain, typically the GRAM domain and sometimes the C2 domain in plants and the integral peroxisomal membrane peroxin Pex24p domain in oomycetes.[1]

Structure

The VASt domain structurally resembles a truncated form of a START domain, but with limited sequence similarity.[1][3] While VASt is a member of the Bet v1-like superfamily, it is unclear if it evolved from the same ancestral domain as the START domain or is an example of convergent evolution.[1]

The domain is highly conserved across all eukaryotes and is typically present in only one copy in VASt domain-containing proteins.[1] Like the START domain, the VASt domain consists of a helix-grip fold structure. The pocket formed is large enough to bind one lipid such as cholesterol,[4] 25-hydroxycholesterol[5] or ergosterol.[2][3]

Analysis of the crystal structure of unbound and bound forms of VASt domains in lipid transfer proteins anchored at a membrane contact site (LAMs) from yeast revealed that the domain contains an accessible hydrophobic cavity."[3][5] Upon sterol binding of the cavity, the entry point is closed or partially closed to the outside.

Human proteins containing the VASt domain

The sole proteins containing this domain identified in human are GRAMD1A/Aster-A, GRAMD1B/Aster-B and GRAMD1C/Aster-C (with the VASt domain referred to as an Aster domain[4]). These sterol transfer proteins together with GRAMD2A and GRAMD2B are LAM family proteins, although the latter two lack the VASt domain.[6] Like LAM proteins, GRAMD1 proteins preferentially transfer sterols.[3][4]

References

  1. 1 2 3 4 5 Khafif M, Cottret L, Balagué C, Raffaele S (2014). "Identification and phylogenetic analyses of VASt, an uncharacterized protein domain associated with lipid-binding domains in Eukaryotes". BMC Bioinformatics. 15: 222. doi:10.1186/1471-2105-15-222. PMC 4082322. PMID 24965341.
  2. 1 2 Horenkamp FA, Valverde DP, Nunnari J, Reinisch KM (2018). "Molecular basis for sterol transport by StART-like lipid transfer domains". EMBO J. 37 (6): e98002. doi:10.15252/embj.201798002. PMC 5852651. PMID 29467216.
  3. 1 2 3 4 Horenkamp FA, Valverde DP, Nunnari J, Reinisch KM (2018). "Molecular basis for sterol transport by StART‐like lipid transfer domains". EMBO J. 37 (6): e98002. doi:10.15252/embj.201798002. PMC 5852651. PMID 29467216.
  4. 1 2 3 Sandhu J, Li S, Fairall L, Pfisterer SG, Gurnett JE, Xiao X, Weston TA, Vashi D, Ferrari A, Orozco JL, Hartman CL, Strugatsky D, Lee SD, He C, Hong C, Jiang H, Bentolila LA, Gatta AT, Levine TP, Ferng A, Lee R, Ford DA, Young SG, Ikonen E, Schwabe JW, Tontonoz P (2018). "Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells". Cell. 175 (2): 514–529.e20. doi:10.1016/j.cell.2018.08.033. PMC 6469685. PMID 30220461.
  5. 1 2 Jentsch JA, Kiburu I, Pandey K, Timme M, Ramlall T, Levkau B, Wu J, Eliezer D, Boudker O, Menon AK (2018). "Structural basis of sterol binding and transport by a yeast StARkin domain". J. Biol. Chem. 293 (15): 5522–5531. doi:10.1074/jbc.RA118.001881. PMC 5900764. PMID 29463678.
  6. ↑ Besprozvannaya M, Dickson E, Li H, Ginburg KS, Bers DM, Auwerx J, Nunnari J (February 2018). "GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells". eLife. 22 (7): e31019. doi:10.7554/eLife.31019. PMC 5823543. PMID 29469807.
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