The ABCs of CBS

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Science  06 Feb 2004:
Vol. 303, Issue 5659, pp. 731
DOI: 10.1126/science.303.5659.731c

The analysis of sequence motifs shared by diverse proteins often provides important information about protein function. One such motif is the cystathionine β-synthase (CBS) domain, a stretch of 60 amino acids that occurs—usually as tandem pairs—in more than a thousand proteins. Hereditary disease-causing mutations in CBS domains have been identified in several human proteins, including AMP-activated protein kinase (Wolff-Parkinson-White syndrome) and IMP dehydrogenase (retinitis pigmentosa), but the functional role of this structural motif has been unclear.

Through biochemical analyses of CBS domains derived from several representative proteins, Scott et al. show that tandem pairs of CBS domains form allosteric binding sites for adenosine-containing ligands and that binding is impaired by disease-associated mutations. In the case of AMP-activated protein kinase, tandem pairs of CBS domains in the enzyme's γ2 subunit appear to provide two binding sites for AMP and ATP, a finding consistent with modeling and mutagenesis work by Adams et al. Localization of the nucleotide binding sites in this enzyme, which is a key player in energy metabolism, may facilitate drug development efforts in diabetes and obesity. — PAK

J. Clin. Invest. 113, 274 (2004); Protein Sci. 13, 155 (2004).

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