CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations

摘要: CBS domains are defined as sequence motifs that occur in several different proteins all kingdoms of life. Although thought to be regulatory, their exact functions have been unknown. However, importance was underlined by findings mutations conserved residues within them cause a variety human hereditary diseases, including (with the gene mutated parentheses): Wolff-Parkinson-White syndrome (γ2 subunit AMP-activated protein kinase); retinitis pigmentosa (IMP dehydrogenase-1); congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter (CLC chloride channel family members); homocystinuria (cystathionine β-synthase). kinase is sensor cellular energy status activated AMP inhibited ATP, but location regulatory nucleotide-binding sites (which prime targets for drugs treat obesity diabetes) not characterized. We now show tandem pairs from kinase, IMP dehydrogenase-2, CLC2, cystathionine β-synthase bind AMP, or S-adenosyl methionine,while diseases impair this binding. This shows act, most cases, sensors and, such, represent newly identified class binding domain adenosine derivatives.