PROSITE documentation PDOC52050

WYL domain profile

Survival of all organisms critically relies on the ability to regulate the expression of genes in the correct spatio-temporal context. This regulation is orchestrated by transcription factors (TFs) and other proteins that are able to integrate environmental cues, leading to activation or repression of genes. In addition to controlling cell division and growth, in bacteria, TFs enable adaptation to changing food sources and environmental stresses.

The WYL (named for three conserved amino acids found in a subset of domains of this superfamily) domain is a nucleotide-sensing module that controls the activity of TFs involved in the regulation of DNA damage response and phage defense mechanisms in bacteria. While the identified phage defense regulators are transcriptional repressors, those identified to date as associated with genotoxic stress act as activators. WYL-containing proteins are widespread in bacteria and act as regulators in multiple cellular contexts. In terms of domain architectures, WYL domains are most frequently associated with different predicted DNA-binding N-terminal winged helix-turn-helix (wHTH) domains. However, WYL domains also show fusions to several enzymatic domains. WYL-containing proteins are classified into nine classes according to their domain co-occurrence and architecture. The majority of WYL-containing proteins are grouped into the A and C categories. The class A features an N-terminal wHTH domain followed by a WYL and a C-terminal extension of the WYL (WCX) domain, and predominates in Actinobacteria and Proteobacteria. Class C can be considered a subset of class A, as it consists of proteins where two class-A proteins are naturally fused. Proteins in the second largest group, class B, also contain N-terminal wHTH domains linked to WYL domains. But these proteins lack WCX domains. Class B predominates in Proteobacteria. The D, E and F class proteins feature the same wHTH-WYL-WCX architecture as in the A/C classes but differ in sequence and connecting regions. The remaining classes lack the wHTH domain and, therefore, most likely do not function as TFs (less than 10%) [1,2,3,4,5].

The WYL domain adopts an Sm-like fold, featuring a five-stranded antiparallel β-sheet with a 5-1-2-3-4 topology preceded by an α-helix. The strands are strongly curved and the middle β2-strand is almost twice the length of the other five, causing it to arch back over itself and resulting in a β-sandwich topology, where β-strands 5-1-2 make up one half and strands 2-3-4 the other. Middle strand β2 is participating in both and connects the two halves. The eponymous WYL residues are located in β3, with the highly conserved tyrosine pointing away from the hydrophobic core (see <PDB:6SJ9>) [2,5].

Some proteins known to contain a WYL domain are listed below:

• Caulobacter crescentus DriD (for DeoR inducer of didA), an SOS response- independent transcriptional activator of a cell division inhibitor protein.
• Mycobacteria PafBC (for proteasome accessory factors B and C), form a heterodimeric transcriptional activator responsible for upregulating the majority of genes induced by DNA damage.
• Bacteria CapW (for CBASS-associated protein with WYL domain) proteins, transcriptional repressors that bind the promoter region of their cognate CBASS operon to inhibit expression of CBASS genes.
• Bacteria transcription repressor BrxR (BREX regulator).
• mycobacteria SiwR (for stress-involved WYL domain-containing regulator), forms a homodimeric transcription factor and, upon genotoxic stress, upregulates two genes encoding proteins of the DinB/YfiT-like putative metalloenzymes superfamily (DinB superfamily).

The profile we developed covers the entire WYL domain.