Molecular recognition by the KIX domain and its role in gene regulation

Abstract

The kinase-inducible domain interacting (KIX) domain is a highly conserved independently folding three-helix bundle that serves as a docking site for transcription factors, whereupon promoter activation and target specificity are achieved during gene regulation. This docking event is a harbinger of an intricate multi-protein assembly at the transcriptional apparatus and is regulated in a highly precise manner in view of the critical role it plays in multiple cellular processes. KIX domains have been characterized in transcriptional coactivators such as p300/CREB-binding protein and mediator of RNA polymerase II transcription subunit 15, and even recQ protein-like 5 helicases in various organisms. Their targets are often intrinsically disordered regions within the transactivation domains of transcription factors that attain stable secondary structure only upon complexation with KIX. In this article, we review the KIX domain in terms of its sequence and structure and present the various implications of its ability to act as a transcriptional switch, the mechanistic basis of molecular recognition by KIX, its binding specificity, target promiscuity, combinatorial potential and unique mode of regulation via allostery. We also discuss the possible roles of KIX domains in plants and hope that this review will accelerate scientific interest in KIX and pave the way for novel avenues of research on this critical domain.

A Repressor Protein Complex Regulates Leaf Growth in Arabidopsis

“…In animals and yeast, KIX protein domains are present mainly in transcriptional coactivator proteins such as HAT or MEDIATOR (MED) subunit proteins (Radhakrishnan et al, 1997;Yang et al, 2006) and mediate the interaction with activation domains of transcription factors (Jedidi et al, 2010). In Arabidopsis, 11 proteins containing KIX-like domains have been described, including not only CBP/p300-like proteins (KIX3, KIX4, KIX5, and KIX7) and MED15-like proteins (KIX1 and KIX6) but also proteins such as KIX8 or KIX9 that have no characterized domain other than a KIX domain (Thakur et al, 2013(Thakur et al, , 2014. KIX8 and KIX9 do not have similarity with MED15 or HATs outside the KIX domain.…”

Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif

“…We demonstrate that this part of the IBD serves as a recognition interface for an intrinsically disordered consensus motif, whereby LEDGF/p75 can act as a chromatin tethering factor for its binding partners. Use of a single interface for several protein-protein interactions with intrinsically disordered regions is analogous to other transcription regulators such as the kinase-inducible domain interacting (KIX) domain 63 . HIV has evolved an alternative way to bind this recognition interface and usurp the elegant molecular tethering mechanism of LEDGF/p75 to achieve efficient integration.…”

Dissecting allosteric effects of activator–coactivator complexes using a covalent small molecule ligand

“…The interaction of a second ligand, phosphorylated kinase-inducible domain (pKID) of CREB, is enhanced (up to twofold) by the presence of MLL and several elegant studies have documented allosteric communication between the two binding sites (11-15). However, the relatively modest affinities (micromolar) of the native complexes and the aggregation propensities and the promiscuous binding profiles of the transcriptional activation domains have hampered kinetic dissection of this and other complexes (16,17).The coactivator CBP exists across metazoans (18)(19)(20) and is a transcription hub that interacts with numerous transcriptional activators, using several discrete domains (21,22). The KIX domain within CBP is a 90-residue motif that consists of a threehelix bundle along with two 3 10 helices (12).…”

“…The coactivator CBP exists across metazoans (18)(19)(20) and is a transcription hub that interacts with numerous transcriptional activators, using several discrete domains (21,22). The KIX domain within CBP is a 90-residue motif that consists of a threehelix bundle along with two 3 10 helices (12).…”