Seminar

CBS domain proteins: structure, function, and pathology in humans

Alfonso Martínez de la Cruz, PhD

The cystathionine beta-synthase (CBS) domains are structural motifs found in more than 30000 proteins in all species from bacteria to humans. They were first identified in 1997 as conserved sequence regions and named after cystathionine beta synthase, one of the enzymes they are found in. CBS domains are present in a wide variety of human proteins such as inosine monophosphate dehydrogenase, voltage gated chloride channels and AMP-activated protein kinase (AMPK), where they regulate the activity of associated enzymatic and transporter domains in response to binding molecules with adenosyl groups such as AMP and ATP, or s-adenosylmethionine. Mutations in human CBS domains lead to rare genetic metabolic diseases like homocystinuria, Wolff- Parkinson-White syndrome, retinitis pigmentosa, or familial hypomagnesaemia, but also to more prevalent pathologies including several types of cancers and cognitive disorders associated to Alzheimer disease or Down syndrome.   In this seminar, Dr. Martínez de la Cruz will introduce some of the advances that they have achieved in the recent years in comprehending the structural basis underlying the regulation exerted by CBS domains on two protein families: (i) the cystathionine beta-synthase, the key enzyme of transsulfuration and (ii) the magnesium transporters of the Cyclin M family. The effect of pathogenic mutations and possible personalized structure-based therapeutical strategies will be discussed.