Structural and functional study of FK domain of Fstl1

Abstract

Fstl1 is a TGF‐β superfamily binding protein which involved in many pathological processes. The function of Fstl1 has been widely elucidated, but its structural characterization has not been explored. Here we solved the high‐resolution crystal structure of FK domain of murine Fstl1, analyzed its unique characteristics, and investigated its contribution to the function of full‐length Fstl1. We found that Fstl1‐FK forms a stable dimer in both solution and crystal, which suggest that this protein may function as a dimer during its interaction with TGF‐β, a molecule known to form dimer during activation process. We also found this FK domain is indispensable for the proper function of Fstl1 during the transduction of TGF‐β signaling. These observations provide important insights into the understanding of Fstl1 and may facilitate the exploration of this molecule in clinical study.

Follistatin-Like Proteins: Structure, Functions and Biomedical Importance

“…They can follow either before the FSD, or in the N-terminal region (ND), or after it. Along with the amino-acid-enriched region, the C-terminal part usually contains an immunoglobulin-like domain (Ig) or an area that is homologous to C-like domain of von Willebrand factor (VWFC) (Figure 2) [1,2]. It should be mentioned that these domains of follistatin-like proteins are a characteristic structural element of all proteins of the osteonectin family (SPARC) [30,[44][45][46].…”

“…It contains two common modules with follistatin and two Kazal-like domains in its structure, besides the re- Despite a specific homology, follistatin-like proteins also have certain differences in the structure of the primary, secondary, or quaternary protein structures. Thus, the structure of FSTL-1 contains a common secretory signal, a follistatin-like domain, a duplicated EF-hand domain, and a VWFC region (Figure 2) [1,2,44]. This protein is found in two differentially glycosylated isoforms with similar functional activity in humans and animals [30,45].…”

“…Nowadays there are five types of follistatin-like proteins: FSTL1, IGFBP7(FSTL2), FSTL3, FSTL4 and FSTL5, having defined the similarities and differences in the domain of classification that represent their specificity [1][2][3]. Homologues of follistatin are expressed in almost all organ systems and tissues (Figure 1), possess the paracrine and autocrine activity, and the nature of their expression changes depending on the severity of pathological processes, including cardiovascular diseases (CVD) [4][5][6][7][8][9], diseases of the respiratory system [10][11][12][13][14][15][16], cancer progression [17][18][19][20][21][22][23][24] and inflammatory diseases [23,[25][26][27][28][29].…”

Follistatin-like 1 promotes proliferation of matured human hypoxic iPSC-cardiomyocytes and is secreted by cardiac fibroblasts

“… 20 Furthermore, cardioprotective and angiogenic effects of FSTL1 have been reported. 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 FSTL1 is a 308 amino acid glycoprotein of the SPARC protein family, with three N-glycosylation sites, 27 , 29 , 30 , 31 with one (N180) being critically linked to the role of FSTL1 in cardiac regeneration. 31 Additionally, an increase in secretion of FSTL1 with higher molecular weight, likely due to protein glycosylation, could be observed in mouse serum and myocardium after myocardial infarction.…”

Inhibition of long non-coding RNA HOXA11-AS against neuroinflammation in Parkinson's disease model via targeting miR-124-3p mediated FSTL1/NF-κB axis

“…Follistatin-like 1 (FSTL1) is a TGF-β superfamily binding protein that is proved to regulate the pathological process of multiple diseases [ 19 ]. Recent studies have shown that FSTL1 facilitates the inflammatory responses and cartilage degradation by activating NF-kappa B(NF-κB) signaling pathways in osteonecrosis of the femoral head (ONFH) model [ 20 ].…”