SLC37A2

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SLC37A2 (solute carrier family 37 member 2) is an endoplasmic reticulum (ER) membrane glucose-6-phosphate (G6P) uniporter belonging to the solute carrier family 37. Unlike its paralog SLC37A4 (the canonical glucose-6-phosphate transporter involved in blood glucose homeostasis), SLC37A2 transports G6P independently of inorganic phosphate antiport and does not couple to glucose-6-phosphatase enzymatic activity. It plays roles in metabolic regulation, immune function, and bone metabolism.

Function

SLC37A2 acts as a uniporter that facilitates the transport of glucose-6-phosphate (G6P) across the endoplasmic reticulum (ER) membrane independently of inorganic phosphate gradients. Unlike other members of the SLC37 family, which function as phosphate-linked antiporters, SLC37A2 does not couple G6P transport to phosphate exchange or to glucose-6-phosphatase activity. It has a unique transport mechanism, operating through conformational changes between ER luminal-open and cytosolic-open states to facilitate the movement of G6P. SLC37A2 is implicated in metabolic regulation and inflammation in macrophages, highlighting a role that extends beyond classical glucose homeostasis managed by SLC37A4 (G6PT)^[1].

Mutations linked to glycogen storage diseases map to critical functional residues, offering insights into disease mechanisms. Loss of SLC37A2 function in mice was seen to lead to dysregulated bone metabolism, characterized by high bone mass, which implicates it as a potential therapeutic target in metabolic bone diseases.

Structural basis of function

The structural basis of the uniport mechanism of SLC37A2 is revealed through cryo-EM structures, which show the protein in two main conformational states: an ER luminal-open state and a cytosolic-open state. SLC37A2 forms a dimer, with each protomer containing 12 transmembrane helices, creating the transport pathway. Some key features are listed below:

G6P binding site: The glucose-6-phosphate (G6P) binding site in SLC37A2 is formed by conserved residues that interact specifically with the phosphate and hydroxyl groups of G6P. Residues such as tyrosine and tryptophan coordinate the recognition and specificity of G6P at this site. This precise coordination enables selective binding and transport of G6P by the transporter.

Conformational Dynamics: SLC37A2 adopts at least two major conformations captured by cryo-EM: an ER luminal-open state and a cytosolic-open state. These conformational changes are driven by the rigid-body movements of transmembrane helix bundles, which alternately expose the substrate-binding site to either side of the ER membrane, enabling the uniport transport mechanism.

Local alterations have also been observed for TM7 and TM10 of human GLUTs44, supporting the flexible dynamics of the C-domain in substrate binding and transport.

Dimeric Architecture: SLC37A2 functions as a dimer, with each protomer containing 12 transmembrane helices. The dimer interface provides structural stability, but each protomer independently performs substrate transport through the alternating access mechanism.

Transport Mechanism (Uniporter): Unlike antiporters that exchange substrates (e.g., glucose-6-phosphate for inorganic phosphate in SLC37A4), SLC37A2 facilitates uniport or facilitated diffusion of G6P across the ER membrane without coupling to phosphate gradients. This is based on conformational cycling between the two states mentioned.

Disease-Linked Residues: Mutations associated with glycogen storage diseases map to key residues involved in G6P binding or conformational transitions, highlighting their functional importance for transport activity and the physiological role of SLC37A2.

Summary

SLC37A2 is an endoplasmic reticulum membrane glucose-6-phosphate (G6P) uniporter belonging to the solute carrier family 37. Structurally, it forms a stable dimer with each protomer containing 12 transmembrane helices that undergo conformational changes between ER luminal-open and cytosolic-open states, enabling selective G6P transport via an alternating access uniporter mechanism. The G6P binding site is formed by conserved residues coordinating phosphate and hydroxyl groups. Unlike its paralog SLC37A4, SLC37A2 functions independently of inorganic phosphate exchange and is not inhibited by chlorogenic acid. Physiologically, it plays crucial roles in immune cell metabolism and bone homeostasis by facilitating G6P transport in specialized organelles such as tubular secretory lysosomes in osteoclasts. Mutations affecting its transport function may contribute to metabolic dysregulation, highlighting its emerging biological significance beyond classical glucose homeostasis.

References

1. ↑ Ihara K, Nomura A, Hikino S, Takada H, Hara T. Quantitative analysis of glucose-6-phosphate translocase gene expression in various human tissues and haematopoietic progenitor cells. J Inherit Metab Dis. 2000 Sep;23(6):583-92. PMID:11032333 doi:10.1023/a:1005677912539