PROSITE documentation PDOC50953

KID domain profile

Transcriptional activators are believed to stimulate gene expression via protein-protein interactions with the basal machinery. The cAMP-regulated transcription factor CREB has been shown to stimulate target gene expression, in part by associating with the coactivator paralogs p300 and CREB binding protein (CBP). The CREB transactivation domain is bipartite, consisting of a kinase-inducible domain (KID) and a glutamine-rich constitutive activator termed Q2 which synergize to stimulate target gene expression in response to cAMP. Ser-133 phosphorylation of CREB within the KID domain promotes target gene activation via complex formation with the KIX domain (see <PDB50952>) of the CBP and P300 coactivators, whereas concurrent phosphorylation of the CREB KID domain at Ser-142 inhibits transcriptional induction. Phospho-Ser-133 stabilizes whereas phospho-Ser-142 disrupts secondary structure-mediated interactions between CREB and CBP/P300. The about 60-residue KID domain is found associated with a basic-leucine zipper (bZIP) domain (see <PDOC00036>) [1,2].

The solution structure of the KID:KIX complex reveals that the KID domain, largely unstructured in the free state, folds into two mutually perpendicular helices, αA and αB, upon binding to the KIX domain (see <PDB:1KDX; B>), allowing the newly formed amphipathic helix αB in KID to form extensive contacts with hydrophobic residues lining a central groove in KIX (see <PDB:1KDX>). Phospho-Ser-133 forms direct contacts with residues in KIX and these contacts are further stabilized by hydrophobic residues in the KID domain which flank phospho-Ser-133. Phospho-Ser-142 was found to inhibit complex formation by interfering with hydrophobic interactions between helix αB in the KID domain and the hydrophobic groove in the KIX domain. Ser-142 phosphorylation may additionally destabilize the αB helix and thereby block binding of CREB to CBP/P300. The sequences of KID domains are highly conserved throughout the region that interacts with the KIX domain, but show little similarity outside this region. Many of the conserved amino acids appear to play primarily a structural role, facilitating formation of the amphipathic αB helix and preserving the hydrophobic contacts with the binding groove of the KIX domain [2,3].

The profile we developed spans the entire KID domain.