CBB Seminar
Monday, Nov. 27, at 11 am
Bldg. 38A, 8th floor conference room.

Small-molecule-binding domains: How many and how important?

Vivek Anantharaman

Many aspects of central cellular functions such as metabolism, solute transport 
and signal transduction are regulated, in part, via binding of small molecules by 
specialized domains - the SMBDs (Small Molecule Binding Domains). SMBDs are known 
to participate in ligand recognition both in intracellular and extracellular 
contexts. 

In an exploration of extracellular ligand recognition a novel domain common to 
diverse bacterial receptors and eukaryotic calcium channel subunits (the Cache 
domain) was discovered. Its potential role in regulation of numerous signaling 
activities will be presented.

A detailed study of intracellular SMBDs was carried out using sensitive methods 
for sequence profile analysis and protein structure comparison. The (near) 
complete proteomes of 25 organisms from the 3 superkingdoms of life (bacteria, 
archaea and eukaryotes) were searched for all occurrences of 20 intracellular 
small-molecule-binding domains (SMBDs) that are represented in at least two of the 
superkingdoms. In many proteomes, particularly those of free-living bacteria and 
archaea, they are present in multiple versions and fused to various enzymatic, 
transport-related and signal-transducing domains whose activity the SMBDs are 
known or predicted to regulate via small molecule binding. The SMBDs appear to 
show some specialization in the regulation of distinct cellular processes. Using 
this information and the 'guilt by association approach', the identification of 
SMBDs results in the prediction of functions and the mode of regulation for a 
large number of previously uncharacterized proteins. Three previously unnoticed 
SMBDs were predicted, the 4VR domain (after 4-vinyl reductase), the NIFX domain 
(after NifX protein involved in nitrogen fixation) and the 3H domain (so named 
after three conserved histidines). The organism-wise demography and the 
evolutionary trends in the architectural engineering of SMBD- containing proteins 
will also be presented. Through sequence and structure comparisons, some early 
events in the origin and evolution of SMBDs will be reconstructed.