Fyn protein

Ilangumaran, S., Ami, S., van Echten-Deckert, G., Borisch, B., and Hoessli, D. C. (1999). Microdomain-dependent regulation of Lck and Fyn protein-tyrosine kinases in T lymphocyte plasma membranes. Mol. Biol. Cell 10(4), 891-905. 

A more detailed picture of the folding of the SH3 (Src homology 3) domain of the Fyn protein kinase has been obtained by relaxation dispersion experiments.93 9 SFI3 domains bind proline-rich sequences and are key components of proteins involved in protein tyrosine kinase signalling pathways. The folding of the SFI3 domain of the Fyn protein kinase has been extensively characterized by stopped-flow and NMR experiments. CPMG relaxation dispersion analysis revealed that the Fyn SH3 domain is essentially a three-state folder with an intermediate state. 

Samelson LE, Phillips AF, Luong ET, Klausner RD Association of the fyn protein-tyrosine kinase with the T-cell antigen receptor. Proc Natl Acad Sci USA 1990 87 4358-4362. 

Ley SC, Marsh M, Bebbington CR, Proudfoot K, Jordan P Distinct intracellular localization of Lck and Fyn protein tyrosine kinases in human T lymphocytes. J Cell Biol 1994 125 639-649. 

Fig. 13.36 Proton NOESY spectrum of the SH3 domain of the Fyn protein. Adapted from P. J. Hore, Nuclear magnetic resonance, Oxford Chemistry Primers 32, Oxford University Press, Oxford (1995).

Fyn is a nonreceptor tyrosine kinase related to Src that is frequently found in cell junctions. Die protein is N-myristoylated and palmitoylated and thereby becomes associated with caveolae-like membrane microdomains. Fyn can interact with a variety of other signaling molecules and control a diversity of biological processes such as T cell receptor signaling, regulation of brain function, and adhesion mediated signaling. 

The unique domain following the SH4 domain from the N-terminus is a region with considerable variation in the amino acid sequences among different Src family members. This unique domain may be involved in protein-protein interactions. For example, the unique region of Lck is linked to CD4 and CD8, while those of Fyn and Lyn may be associated with the T- and B-cell antigen receptors. 

Due to the ready accessibility of SH2 domains by molecular biology techniques, numerous experimentally determined 3D structures of SH2 domains derived by X-ray crystallography as well as heteronuclear multidimensional NMR spectroscopy are known today. The current version of the protein structure database, accessible to the scientific community by, e.g., the Internet (http //www.rcsb.org/pdb/) contains around 80 entries of SH2 domain structures and complexes thereof. Today, the SH2 domain structures of Hck [62], Src [63-66], Abl [67], Grb2 [68-71], Syp [72], PLCy [73], Fyn [74], SAP [75], Lck [76,77], the C- and N-terminal SH2 domain ofp85a [78-80], and of the tandem SH2 domains Syk [81,82], ZAP70 [83,84], and SHP-2 [85] are determined. All SH2 domains display a conserved 3D structure as can be expected from multiple sequence alignments (Fig. 4). The common structural fold consists of a central three-stranded antiparallel ft sheet that is occasionally extended by one to three additional short strands (Fig. 5). This central ft sheet forms the spine of the domain which is flanked on both sides by regular a helices [49, 50,60]. 

Src is the prototype of the superfamily of protein tyrosine kinases and was one of the first protein kinases to be characterized by various genetic, cellular, and structure-function studies to help imderstand its role in signal transduction pathways as well as in disease processes, including cancer, osteoporosis, and both tumor- and inflammation-mediated bone loss [28-38]. In fact, studies on Src provided some of the first evidence correlating protein kinase activity and substrate protein phosphorylation in the regulation of signal transduction pathways relative to normal cellular activity as well as mahgnant transformations. Src family kinases include Fyn, Yes, Yrk, Blk, Fgr, Hck, Lyn,... 

Also related to Src kinase structural biology have been studies on two SFKs, namely Lck and Fyn. Importantly, the X-ray structure of Lck kinase was the first SFK determined [64] as complexes with AMP-PNP, staurosporine and PP2. Furthermore, a Fyn kinase-staurosporine complex has been recently described [65]. Extrapolating from the above Src kinase inhibitor crystal structures with respect to the hydrophobic specificity pocket and the active conformation of the protein to bind ATP-competitive inhibitors of varying templates and functional group elaboration, a working hypothesis of known Src kinase inhibitors (vide infra) can be suggested (Fig. 4). 

Fig. 16.11. Model of the association of Fyn kinase with the NMDA receptor The NMDA receptor is shown as a tetramer of NRl and NR2 subunits. The C-terminal tail of NR2 interacts with PDZ2 of PSD-95. The protein tyrosine kinase Fyn is assumed to bind to PDZ3 of PSD-95 via its SH2 domain. Fyn also is anchored to the ceU membrane via its myristoylated N-terminus. GK guanylate kinase domain of PSD-95. According to Sala and Sheng (1999), with permission.

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