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Abstract: Fibroblast growth factors (FGF) are a class of 22 polypeptide growth factors which is known to stimulate various cellular functions like cell proliferation, wound healing etc. They carry out these functions by binding to different FGF receptors (FGFR1-4). FGF11-14 is also known as fibroblast growth factor homologous factors (FHFs) since they are structurally as well as sequentially similar but functionally are very different. Like FGFs, FHFs also contain a core region of 120-130 residues and binds to heparin. But they show no affinity towards FGFRs and lack leader sequence, so they remain intracellular. Only a few residues which are present only in FHFs are responsible for these differences and among them Val95and Arg52 residues are the most significant ones. So we tried to replace Arg with Gly residue and check the effect of mutation on folding and stability of the protein
. INTRODUCTION
Fibroblast growth factor (FGF) is known to mankind for over last 40 years. Early in 1970s it was discovered that preparations which contained FGF showed affects in growth and wide range of cells. They are also known to stimulate collateral vascularization and recovery from ischemia. FGF has capacity to enhance wound healing and cartilage repair in the field of neurology (1). FGF are a family consisting of 23 members (FGF1-23). They are also found in invertebrates such as Drosophila melanogaster implying that FGF arose in early metazoan evolution. Crystal structure of FGFs showed its similarity with interleukins-1α and 1β. Although the family members and interleukins shows no sequence similarity but both adopts a β-trefoil structure similar to those found in trypsin inhibitors, ricin like toxins (2).
FGF carries out these functions by activating FGF receptors (FGFR). FGFRs consists of three extracellular immunoglobulin like structures (DI, DII, DIII), one transmembrane domain and one intracellular tyrosine kinase domain Fibroblast growth factor homologous factor 1, 2, 3, 4 which are also dedicated as FGF 12, 13, 11, 14 share sequence and structural similarity with the traditional FGFs. But they are functionally very different. Leader sequence is very prominent in case of FGFs (except FGF1) but FHFs lack these sequences and are secreted intracellularly. FHFs also do not have any affinity towards FGFR. They rather shows affinity towards voltage gated sodium channels (VGSC) and neuronal MAP kinase scaffold proteins. They contain basic residues which act as nuclear localization signals.(4)
FHF mutagenesis studies revealed that Arginine-52 and valine-95 in β4-β5 and β9 strands are conserved in all FHF proteins and not present FGFs. When either of these residues were mutated, it disabled FHF to prevent to VGSC or IB2.