Organized by unstructured motifs
The high degree of conservation in protein sequences thought to be unstructured has hinted that these regions may have important biological functions. Although unstructured regions are widely viewed to be crucial for protein signaling, localization, and stability, their roles in many other settings have remained mysterious. Cermakova
et al
. discovered that prominent members of the transcription elongation machinery are linked through a network of interactions involving transcription elongation factor TFIIS N-terminal domains (TNDs) and conserved unstructured sequences called “TND-interacting motifs” (TIMs). The researchers found that mutation of a single TIM in a central organizing protein of this network abolished key protein interactions and induced widespread defects in transcription elongation dynamics. —DJ
Dimerization of many eukaryotic transcription regulatory factors is critical for their function. Regulatory role of an epigenetic reader Lens Epithelium Derived Growth Factor/p75 (LEDGF/p75) requires at least two copies of this protein to overcome the nucleosome-induced barrier to transcription elongation. Moreover, various LEDGF/p75 binding partners are enriched for dimeric features further underscoring functional regulatory role of LEDGF/p75 dimerization. Here, we dissected the minimal dimerization region in the C-terminal part of LEDGF/p75 and using paramagnetic NMR spectroscopy identified the key molecular contacts that helped to refine the solution structure of the dimer. The LEDGF/p75 dimeric assembly is stabilized by domainswapping within the integrase binding domain and additional electrostatic 'stapling' of the negatively charged -helix formed in the intrinsically disordered C-terminal region. We validated dimerization mechanism using structure-inspired dimerization defective LEDGF/p75 variants and chemical cross-linking coupled to mass spectrometry. We also show how dimerization might impact the LEDGF/p75 interactome.
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