Histone deacetylase 6 catalytic domain 2 (HDAC6 CD2)

Histone deacetylase 6 (HDAC6) is a unique member of the Class IIb HDAC family, characterized by its predominantly cytoplasmic localization and the presence of two tandem catalytic domains, CD1 and CD2 (UniProt Q9UBN7). While both domains are structurally similar, the second catalytic domain (CD2) is the primary site responsible for the enzyme's deacetylation activity toward non-histone substrates such as alpha-tubulin, Hsp90, and cortactin (PMID: 22461466). By regulating the acetylation status of these proteins, HDAC6 CD2 plays a critical role in microtubule-based transport, protein degradation via the aggresome pathway, and cellular stress responses (PMID: 27013335). In oncology, HDAC6 is often overexpressed, facilitating the survival of cancer cells by managing misfolded protein stress; thus, selective inhibition of CD2 is a major therapeutic strategy to induce apoptosis while minimizing the toxicities associated with pan-HDAC inhibitors (PMID: 26363458). Beyond cancer, HDAC6 CD2 is a target for neurodegenerative diseases like Charcot-Marie-Tooth and Alzheimer's due to its influence on axonal transport and microtubule stability (PMID: 30104341).

Other names

HDAC6-CD2Second catalytic domain of HDAC6C-terminal catalytic domain of HDAC6HDAC6 domain 2

Selective inhibition of the second catalytic domain (CD2) of HDAC6, which prevents the deacetylation of cytoplasmic substrates like alpha-tubulin and Hsp90, thereby disrupting protein homeostasis and cellular transport (PMID: 22461466).