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Structural studies of metal-dependent hydrolases: Histone Deacetylase 6 and Glutamate Carboxypeptidase II
Shukla, Shivam ; Bařinka, Cyril (advisor) ; Stříšovský, Kvido (referee) ; Kolenko, Petr (referee)
Zinc-dependent hydrolases are a class of metalloenzymes that require zinc ions to catalyse hydrolytic reactions. Structural studies of these enzymes shall provide detailed information about the processing of their natural substrates, domain organization, and overall structural fold. This thesis describes the structural properties of two different metallohydrolases 1) human histone deacetylase 6 (HDAC6) and 2) glutamate carboxypeptidase II (GCPII) by utilizing a different set of biophysical techniques. HDAC6 is a structurally unique multidomain enzyme comprised of unstructured and globular domains. It regulates the plethora of cellular processes by removing an acetyl group from lysine side chains of target proteins. It has been known to deacetylate non-histone substrates such as tubulin, Hsp90, cortactin, and peroxiredoxins. Given its structural complexity, complete structural information of full-length HDAC6 is missing and available information is limited to its globular domains only. Hence, the integrative approach was employed in combining experimental data from several orthogonal biophysical techniques to build an in-solution structural model of HDAC6. The study reports that HDAC6 adopts multiple conformations due to its unstructured regions and exists as an ensemble of conformers in solution....
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