Structure C-Raf

a schematic architecture of human c-raf protein

similarly many other mapkkks, c-raf multidomain protein, several additional domains aid regulation of catalytic activity. on n-terminal segment, ras-binding domain (rbd) , c-kinase homologous domain 1 (c1 domain) found next each other. structures of both conserved domains solved in past decades, shedding light on mechanisms of regulation.

the ras-binding domain displays ubiquitin-like fold (like many other small g-protein associating domains) , selectively binds gtp-bound ras proteins only. (you can see interaction in high detail in pdb box attached article. shows rap1 in complex rbd of c-raf.)

the c1 domain - downstream of ras binding domain - special zinc finger, rich in cysteines , stabilized 2 zinc ions. similar diacylglycerol-binding c1 domains of protein kinase c (pkc) enzymes. unlike pkc, c1 domains of raf family kinases not bind diacylglycerol. instead, interact other lipids, such ceramide or phosphatidic acid, , aid in recognition of activated ras (gtp-ras).

the close proximity of these 2 domains several lines of experimental data suggest act single unit negatively regulate activity of protein kinase domain, direct physical interaction. historically, autoinhibitory block labelled cr1 region ( conserved region 1 ), hinge region being named cr2, , kinase domain cr3. unfortunately, precise structure of autoinhibited kinase remains unknown.

between autoinhibitory domain block , catalytic kinase domain, long segment - characteristic raf proteins - can found. highly enriched in serine amino acids, precise sequence poorly conserved across related raf genes. region appears intrinsically unstructured, , flexible. role act natural hinge between rigidly folded autoinhibitory , catalytic domains, enabling complex movements , profound conformational rearrangements within molecule. hinge region contains small, conserved island of amino acids, responsible 14-3-3 protein recognition, when critical serine (ser259 in human c-raf) phosphorylated. second, similar motif found on extreme c-terminus (centered around phosphorylatable ser 621) of raf enzymes, downstream of kinase domain.

the c-terminal half of c-raf folds single protein domain, responsible catalytic activity. structure of kinase domain well-known both c-raf , b-raf. highly similar other raf kinases , ksr proteins, , distinctly similar other map3 kinases, such mixed lineage kinase (mlk) family. comprise tyrosine kinase (tkl) group of protein kinases. although features unite catalytic domains protein tyrosine kinases, activity of tkls restricted phosphorylation of serine , threonine residues within target proteins. important substrate of raf kinases (apart itself) mkk1 , mkk2 kinases, activity strictly depends on phosphorylation events performed rafs.