Spot 14 Protein
Created by Shanshan Peng
Spot 14(S14, PDB ID = 3ONT) is a 17-kDa acidic protein that is abundant in liver, white and brown fat, and lactating mammary gland (1,2). S14’s structure was initially elucidated in Mus musculus (3). It belongs to the S14 family (pfam07084), which includes thyroid hormone-inducible hepatic protein S14, Mid1-interacting protein MIG12 and related sequences. The S14 gene is present only in genome of mammalian species and it is evolutionarily conserved (4). Although the molecular function of S14 remains unclear, previous researches indicate that it plays an important role in the regulation of de novo lipid synthesis in lipogenic tissues, especially in lactating mammary gland (5). In humans, hS14 may function as an important modulator of tumorigenesis in human breast by decreasing cell growth and inducing cell death and differentiation (6).
S14 monomer (PDB ID = 3ONT) is a 150 amino acid protein (3). The main body of the S14 monomer is composed of three antiparallel α-helices. Helices 1 and Helices 2 are ∼30 Å in length and helix 3 is ∼60 Å in length. The secondary structure of S14 monomer is showed here. S14 exists as a homodimer and that dimerization depends on a evolutionarily conserved hygrophobic hetad repeat (zipper) near the carboxyl terminus (7). The increased length of helix 3 allows it to interact with an adjacent monomer. Thereby, an antiparallel 4-helix bundle is created by packing the C terminus of helix 3 against the main body of the other monomer to form the homodimer. The S14 dimer is ∼25 × 30 × 75 Å with the monomers related by 2-fold symmetry.
S14 is a small protein(17-kDa) that lacks any well-recognized functional motifs and the protein had not been known to share significant homology with any proteins of established function until recent years (5), making determination of its own function a challenge. Much of the work done on s14 has focused on regulation of its gene, indicating the gene is highly regulated at the transcriptional level by SREBP-1c and ChREBP, transcription factors that activate all genes involved in fatty acid synthesis . Previous investigation into the role of S14 suggested that it serves a regulator in de nove lipogenesis (8). The lack of S14 in different tissues resulted in varying phenotypic effects. In the lactating mammary gland, levels of lipogenesis, specifically the production of mediumchain fatty acids, were decreased, whereas hepatic lipogenesis was increased. The difference may be due to compensation by a paralog of S14 (S14-R or MIG12) which is only expressed in the liver (4). Importantly, S14 knockout mice did not have reduced levels of lipogenic enzymes, so S14 may act in the cytoplasm to affect lipogenesis (5).
Last research demonstrats that S14 can form a heterodimer with MIG12(3). MIG12, a 183 amino acid protein, binds to acetyl-CoA carboxylase(ACC), which induces polymerization and subsequently increases the enzymatic activity of the protein (9). Although S14 and MIG12 share 32% identity, S14 does not bind and activate ACC (9), So S14 probably reduces the activity of MIG12 and/or serve a capping function preventing further polymerization and activation of ACC by MIG12 .
In humans, the S14 gene locus is in the chromosomal region 11q13 which is frequently amplified in breast cancers, indicating that hS14 may function as an important modulator of tumorigenesis. S14 overexpession in MCF-7 human breast cause an inhibition of cell proliferation and of anchorage-independent growth, a marked reduction in the number of viable cells and the induction of differentiation and cell death of these cells(10). Primary breast cancers with low S14 do not survive transit from the lipoprotein lipase(LPL)-rich mammary fat pad to areas devoid ofLPL, such as lymph nodes, and thus do not appear as distant metastases. Thus, S14 is a marker for aggressive breast cancer and a potential therapeutic target as well (11).