The CBS Domain: A Protein Module with an Emerging Prominent Role in Regulation

Abstract

Regulatory CBS (cystathionine β-synthase) domains exist as two or four tandem copies in thousands of cytosolic and membrane-associated proteins from all kingdoms of life. Mutations in the CBS domains of human enzymes and membrane channels are associated with an array of hereditary diseases. Four CBS domains encoded within a single polypeptide or two identical polypeptides (each having a pair of CBS domains at the subunit interface) form a highly conserved disk-like structure. CBS domains act as autoinhibitory regulatory units in some proteins and activate or further inhibit protein function upon binding to adenosine nucleotides (AMP, ADP, ATP, S-adenosyl methionine, NAD, diadenosine polyphosphates). As a result of the differential effects of the nucleotides, CBS domain-containing proteins can sense cell energy levels. Significant conformational changes are induced in CBS domains by bound ligands, highlighting the structural basis for their effects.

Comparative Analysis of 126 Cyanobacterial Genomes Reveals Evidence of Functional Diversity Among Homologs of the Redox-Regulated CP12 Protein

“…CBS domain pair-containing proteins often form homodimers, with two CBS domain pairs assembling into a CBS module with a total of four CBS domains (Baykov et al, 2011). A key question raised by our observations is whether the CP12 CBS domain facilitates the homodimerization of two CP12-CBS proteins or whether the CBS domain in a given CP12 dimerizes with a CBS domain found on some other protein.…”

Structural basis of regulation and oligomerization of human cystathionine β-synthase, the central enzyme of transsulfuration

“…Like the wild-type hCBS, the modified hCBS construct (hCBSOPTΔ516-525) lacking this loop still contains a tandem of CBS motifs (i.e., a Bateman module) in the Cterminal regulatory region (Fig. 1A) (16,23). First, we compared our construct with both the wild-type hCBS and the truncated 45-kDa hCBS lacking the regulatory domain (Fig.…”

Role of CBS and Bateman Domains in Phosphorylation-Dependent Regulation of a CLC Anion Channel

“…Bateman domains in multimeric proteins, including CLCs, dimerize to form a Bateman domain dimer (14)(15)(16)(17)19,20). To determine whether the dimer is required for regulation, we used concatemeric channel constructs generated by fusing two channel monomers C-terminus to N-terminus via a 19-amino-acid linker.…”

“…Bateman domains are found in proteins from all kingdoms of life, play critical cellular regulatory roles, and when mutated cause diverse and serious diseases, including homocystinuria, hypertrophic cardiomyopathy, and retinitis pigmentosa (18)(19)(20)(21). Bateman domains interact with diverse regulatory ligands, including adenosine nucleosides (18), cytoplasmic ions (22), charged membrane domains (23), DNA and RNA (24,25), and other proteins (26).…”

“…Bateman domains interact with diverse regulatory ligands, including adenosine nucleosides (18), cytoplasmic ions (22), charged membrane domains (23), DNA and RNA (24,25), and other proteins (26). Interactions with regulatory ligands induce Bateman domain conformational changes that control protein function (19,21).…”