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Structural Research of Sterol-Sensing Domain (SSD) Proteins

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Sterol-sensing structural domains (SSDs) are found in various membrane proteins and play essential roles in cholesterol metabolism, transportation, and signal transduction. Containing SSD proteins, such as sterol regulatory element binding protein (SREBP) - clearance activating protein (Scap), Niemann Pick release type C1 (NPC1), 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and patched, their structures reveal the importance of a conserved core for sterol dependent function.

Conformational analysis of SSD protein in HMGCR

HMGCR is the rate-limiting enzyme for cholesterol synthesis and a target for cholesterol-lowering statins. TM 2-6 of HMGCR contains a 170 amino acid SSD. Researchers report the cryo-electron microscopic structure of the HMGCR-UBIAD1 complex and find that rearrangements of the TM in the SSD allow the recruitment of proteins that initiate HMGCR degradation, a key reaction in the regulatory system controlling cholesterol synthesis. The rearrangement allowed the recruitment of proteins that initiate HMGCR degradation, a critical reaction in the regulatory system controlling cholesterol synthesis.

Advances in research on SSD protein action mechanisms

Researchers further analyzed the SSD conformation in both HMGCRs to gain insight into the mechanism of the sterol sensing response. By comparing the structure of HMGCR with that of other SSD-containing proteins (Insig-bound Scap), it is hypothesized that SSDs cannot bind to Insigs and resist ERAD when HMGCR adopts conformation B. However, adopting conformation A promotes HMGCR binding to Insig for subsequent ubiquitination and ERAD.

Structural comparison of HMGCR with Insig-bound Scap reveals dynamic features of SSDs.    Figure 1. Structural comparison of HMGCR with Insig-bound Scap reveals dynamic features of SSDs. (Chen H, et al., 2022)

Protein Organism Method Resolution PDB Entry ID
NPC1 Homo sapiens Cryo-EM single particle analysis 3.6 Å 6W5R
NPC1L1 Homo sapiens Cryo-EM single particle analysis 3.34 Å 7N4U
NPC1-NPC2 complex Homo sapiens Cryo-EM single particle analysis 4 Å 6W5V
Delta N-NPC1L1-CLR Homo sapiens Cryo-EM single particle analysis 2.69 Å 7DFW
Delta N-NPC1L1-EZE Homo sapiens Cryo-EM single particle analysis 3.58 Å 7DFZ
Full-length hNPC1L1-Apo Homo sapiens Cryo-EM single particle analysis 3.03 Å 7DF8
Niemann-Pick type C protein NCR1 Saccharomyces cerevisiae S288C X-ray diffraction 3.5 Å 6R4L
Cholesterol-bound NPC1L1 Homo sapiens Cryo-EM single particle analysis 3.58 Å 7N4V
NPC1-like intracellular cholesterol transporter 1 (NPC1L1) Rattus norvegicus Cryo-EM single particle analysis 3.7 Å 6V3F
NPC1L1 mutant-W347R Homo sapiens Cryo-EM single particle analysis 3.33 Å 7N4X
NPC1-like intracellular cholesterol transporter 1 (NPC1L1) in complex with an ezetimibe analog Rattus norvegicus Cryo-EM single particle analysis 3.5 Å 6V3H
Itraconazole-bound NPC1 Homo sapiens Cryo-EM single particle analysis 4.02 Å 6UOX
Niemann-Pick type C protein NPC2 Saccharomyces cerevisiae S288C X-ray diffraction 2.8 Å 6R4M
Niemann-Pick type C protein NPC2 with ergosterol bound Saccharomyces cerevisiae S288C X-ray diffraction 2.9 Å 6R4N
Scap L1-L7 / Fab 4G10 complex focused refinement Gallus gallus Cryo-EM single particle analysis 2.9 Å 7LKF
Scap D435V L1-L7 domain / Fab complex focused map Gallus gallus Cryo-EM single particle analysis 3.5 Å 7LKH
HMGCR-UBIAD1 Complex State 1 Cricetulus griseus Cryo-EM single particle analysis 3.23 Å 8DJM
HMGCR-UBIAD1 Complex State 2 Cricetulus griseus Cryo-EM single particle analysis 3.33 Å 8DJK
Niemann-Pick C1 protein Homo sapiens X-ray diffraction 3.335 Å 5U74
Ptch1 Homo sapiens Cryo-EM single particle analysis 3.9 Å 6DMB
Ptch1 with three mutations L282Q/T500F/P504L Homo sapiens Cryo-EM single particle analysis 4.1 Å 6DMO

Table 1. Structural research of the sterol-sensing domain (SSD) proteins.

Structural analysis is essential to the research of proteins and other biomolecules, and Creative Biostructure's experts use a variety of cutting-edge techniques to provide clients with high-quality structural information, such as X-ray crystallographycryo-electron microscopy (cryo-EM), and NMR spectroscopy.

Whether you need to explore the action mechanisms of SSD proteins involved in cholesterol metabolism and signaling pathways or the structure and functions of other biomolecules, we have the expertise and resources to deliver results beyond your expectations. Please contact us to learn more about our structural analysis services and how we can help advance your research.

References

  1. Chen H, et al. Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain. Nat Commun. 2022. 13(1): 4273.
  2. Wu X, et al. Structural advances in sterol-sensing domain-containing proteins. Trends Biochem Sci. 2022. 47(4): 289-300.
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