VAD1 analog of StAR-related lipid transfer
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{{Infobox protein family
| class =
| Symbol = VASt domain
| Name = VASt domain
| image =
| caption =
| Pfam = PF16016
| Pfam_clan =
| InterPro = IPR031968
| SMART =
| PROSITE =
| MEROPS =
| CATH =
| SCOP =
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD =
| Membranome superfamily =
| Membranome family =
}}
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 ).{{cite journal |vauthors=Khafif M, Cottret L, Balagué C, Raffaele S |title=Identification and phylogenetic analyses of VASt, an uncharacterized protein domain associated with lipid-binding domains in Eukaryotes |journal=BMC Bioinformatics |volume=15 |pages=222 |year=2014 |pmid=24965341 |pmc=4082322 |doi=10.1186/1471-2105-15-222 |doi-access=free }}{{cite journal |vauthors=Horenkamp FA, Valverde DP, Nunnari J, Reinisch KM |title=Molecular basis for sterol transport by StART-like lipid transfer domains |journal=EMBO J. |volume=37 |issue=6|pages=e98002|year=2018 |pmid=29467216 |pmc=5852651 |doi=10.15252/embj.201798002}} 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.
Structure
The VASt domain structurally resembles a truncated form of a START domain, but with limited sequence similarity.{{cite journal |vauthors=Horenkamp FA, Valverde DP, Nunnari J, Reinisch KM |title=Molecular basis for sterol transport by StART‐like lipid transfer domains |journal=EMBO J. |volume=37 |issue=6|pages=e98002|year=2018 |pmid=29467216 |pmc=5852651 |doi=10.15252/embj.201798002}} 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.
The domain is highly conserved across all eukaryotes and is typically present in only one copy in VASt domain-containing proteins. 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,{{cite journal |vauthors=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 |title=Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells |journal=Cell |volume=175 |issue=2|pages=514–529.e20|year=2018 |pmid=30220461 |pmc=6469685 |doi=10.1016/j.cell.2018.08.033}} 25-hydroxycholesterol{{cite journal |vauthors=Jentsch JA, Kiburu I, Pandey K, Timme M, Ramlall T, Levkau B, Wu J, Eliezer D, Boudker O, Menon AK |title=Structural basis of sterol binding and transport by a yeast StARkin domain |journal=J. Biol. Chem. |volume=293 |issue=15|pages=5522–5531|year=2018 |pmid=29463678 |pmc=5900764 |doi=10.1074/jbc.RA118.001881|doi-access=free }} or ergosterol.
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." 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). These sterol transfer proteins together with GRAMD2A and GRAMD2B are LAM family proteins, although the latter two lack the VASt domain.{{cite journal |vauthors=Besprozvannaya M, Dickson E, Li H, Ginburg KS, Bers DM, Auwerx J, Nunnari J |title=GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells |journal=eLife |volume=22 |issue=7 |pages=e31019 |date=February 2018 |pmid=29469807 |pmc=5823543 |doi= 10.7554/eLife.31019 |doi-access=free }} Like LAM proteins, GRAMD1 proteins preferentially transfer sterols.
References
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