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Structural Research of Solute Sodium Symporter (SSS) Family

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The solute sodium symporter (SSS) family consists of integral membrane proteins that use sodium gradients to drive the transport of solutes such as sugars, amino acids, vitamins, nucleosides, inositol, or ions across membranes. The SSS family members have been identified in bacteria, archaea, and eukaryotes. For example, the human sodium/iodine symporter protein (NIS) and sodium/glucose symporter protein (SGLT1) have been associated with diseases such as defective iodine transport or glucose-galactose malabsorption; and the bacterial sodium/proline symporter PutP and sodium/sialic acid symporter SiaT play essential roles in bacterial-host interactions.

Advances in research on SSS family proteins

Understanding the molecular mechanisms of transporter protein function requires detailed structural information. Indeed, X-ray crystallography has made significant progress in understanding channel-type proteins and ion pumps. Most of the experimental evidence for topological arrangements comes from research on the E. coli Na+ /proline symporter protein PutP. Circular dichroism measurements of purified and reconstituted PutP and the use of fixed-point spin labeling and electron paramagnetic resonance (EPR) spectroscopy are used to test the altered structural arrangement of PutP. Information on the spin-labeling morphology is obtained by analyzing the residual mobility of site-specifically linked nitroxide side chains and determining the collision frequencies of nitroxide with nonpolar oxygen and polar CROX.

Structural analysis of SSS family members

SSS proteins have 13 to 15 transmembrane helices (TMS) and usually contain 13 TMS cores, but the number of TMS varies among family members. For instance, PutP has a 13 TMS topology in the periplasmic N-terminus and cytoplasmic C-terminus. Residues essential for substrate and Na+ binding in PutP are present in TMS 2, 7, and 9 and adjacent loops. The researchers report the crystal structure of the SSS family member sodium: galactose homotransporter vSGLT. The approximately 3.0 Å structure contains 14 transmembrane α-helices oriented in the inward-facing conformation, and its core structure consists of an inverted repeat sequence of five TM helices (TM2 to TM6 and TM7 to TM11). Galactose is bound at the center of the core and is isolated from external solution by hydrophobic residues.

Membrane topology and 3D structures of solute/sodium symporter (SSS) family transporters.   Figure 1. Membrane topology and 3D structures of solute/sodium symporter (SSS) family transporters. (Henriquez T, et al., 2021)

Protein Organism Method Resolution PDB Entry ID
Sodium/Sugar symporter with bound Galactose Vibrio parahaemolyticus X-ray diffraction 2.7 Å 3DH4
Substrate-bound outward-open state of a Na+-coupled sialic acid symporter Proteus mirabilis HI4320 X-ray diffraction 2.26 Å 5NVA
Substrate-bound outward-open state of a Na+-coupled sialic acid symporter Proteus mirabilis HI4320 X-ray diffraction 1.95 Å 5NV9
The K294A mutant of vSGLT Vibrio parahaemolyticus X-ray diffraction 2.73 Å 2XQ2
SGLT2-MAP17 complex bound with substrate AMG in the occluded conformation Homo sapiens Cryo-EM single particle analysis 3.33 Å 7YNJ
SGLT2-MAP17 complex in the apo state in the inward-facing conformation Homo sapiens Cryo-EM single particle analysis 3.48 Å 7YNK
SGLT1-MAP17 complex bound with substrate 4D4FDG in the occluded conformation Homo sapiens Cryo-EM single particle analysis 3.26 Å 7YNI
SGLT1-MAP17 complex bound with LX2761 Homo sapiens Cryo-EM single particle analysis 3.2 Å 7WMV
SMCT1 Homo sapiens Cryo-EM single particle analysis 3.5 Å 7SL9
SGLT1 Homo sapiens Cryo-EM single particle analysis 3.4 Å 7SL8
SGLT2-MAP17 complex bound with empagliflozin Homo sapiens Cryo-EM single particle analysis 2.95 Å 7VSI
Bicarbonate transporter complex SbtA-SbtB bound to HCO3- Synechocystis sp. PCC 6803 substr. Kazusa X-ray diffraction 3.2 Å 7EGL
Bicarbonate transporter complex SbtA-SbtB bound to AMP Synechocystis sp. PCC 6803 substr. Kazusa Cryo-EM single particle analysis 2.7 Å 7EGK
A substrate-free glutamate transporter homologue GltTk Thermococcus kodakarensis KOD1 X-ray diffraction 2.7 Å 5DWY
The sodium/iodide symporter (NIS) Rattus norvegicus Cryo-EM single particle analysis 3.3 Å 7UUY
a cysteine-pair mutant (Y113C-P190C) of a bile acid transporter trapped in an outward-facing conformation Yersinia frederiksenii X-ray diffraction 2.861 Å 6LH1
VcINDY-Na+ in amphipol Vibrio cholerae Cryo-EM single particle analysis 3.16 Å 6WU3
VcINDY in complex with terephthalate Vibrio cholerae X-ray diffraction 3.92 Å 6WTX
the divalent anion/Na+ symporter Vibrio cholerae O1 biovar El Tor str. N16961 X-ray diffraction 2.78 Å 5UL9
The divalent anion/Na+ symporter Vibrio cholerae O1 biovar El Tor str. N16961 X-ray diffraction 2.8 Å 5ULE
The sodium/iodide symporter (NIS) in complex with perrhenate and sodium Rattus norvegicus Cryo-EM single particle analysis 3.2 Å 7UUZ
VcINDY-Na-Fab84 in nanodisc Homo sapiens Cryo-EM single particle analysis 3.15 Å 6WW5
VcINDY-apo Vibrio cholerae Cryo-EM single particle analysis 3.23 Å 7T9F
VcINDY-Na+ Vibrio cholerae Cryo-EM single particle analysis 2.83 Å 7T9G
SVCT1 in an apo state Mus musculus Cryo-EM single particle analysis 3.5 Å 7YTY

Table 1. Structural research of the solute sodium symporter (SSS) family.

Creative Biostructure is a renowned organization in the field of structural biology and holds a leading position in providing structural analysis services for membrane proteins. We utilize cutting-edge  X-ray crystallography, and cryo-electron microscopy (cryo-EM) techniques to reveal the complex structures of solute sodium symporter (SSS) family members at high resolution. Through our services, we have greatly advanced the understanding of the functional mechanisms of SSS proteins. If you are interested in our services, contact us now to unleash our advanced capabilities and potential to propel you closer to achieving your scientific goals.

References

  1. Henriquez T, et al. Prokaryotic Solute/Sodium Symporters: Versatile Functions and Mechanisms of a Transporter Family. Int J Mol Sci. 2021. 22(4): 1880.
  2. Jung H. Towards the molecular mechanism of Na (+)/solute symport in prokaryotes. Biochim Biophys Acta. 2001. 1505(1): 131-143.
  3. Abramson J, Wright EM. Structure and function of Na (+)-symporters with inverted repeats.Curr Opin Struct Biol. 2009. 19(4): 425-432.

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