Catalysis and substrate selection by histone/protein lysine acetyltransferases

Abstract

Reversible protein acetylation is controlled by the opposing actions of protein lysine acetyltransferases and deacetylations. Recent developments on the structure and biochemical mechanisms of histone acetyltransfers (HATs) have provided new insight into catalysis and substrate selection. Diverse families of HATs appear to perform a conserved mechanism of acetyl-transfer, where the lysine-containing substrate directly attacks enzyme-bound acetyl-CoA. The ability of HATs to form distinct multi-subunit complexes provide a means to regulate HAT activity by altering substrate specificity, targeting to specific loci, enhancing acetyltransferase activity, restricting access of non-target proteins, and coordinating the multiple enzyme activities of the complex. In the case of newly discovered Rtt109 HAT, association with distinct histone chaperones directs substrate selection between N-terminal lysines (H3K9, H3K23) and those (H3K56) within the histone fold domain. Moreover, the ability of some HATs to utilize longer chain acyl-CoA (i.e. propionyl-CoA) as alternative substrates suggests a potential direct link between the metabolic state of the cell and transcriptional regulation.

Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups

“…These alternative modifications are likely derived from cellular pools of propionyl-CoA and butyryl-CoA as acetyltransferases can use these substrates with reasonable efficiency (for review see Refs. 56,57). Whether such variants have biologically significant roles, or are the consequence of the imperfection of enzymatic processes in their ability to distinguish small structural variants of substrates, remains a topic of interest.…”

Subunit Composition and Substrate Specificity of a MOF-containing Histone Acetyltransferase Distinct from the Male-specific Lethal (MSL) Complex

“…We observe that in contrast to the MSL-associated MOF, which acetylates almost exclusively nucleosomal histone H4 on lysine 16, NSL-associated MOF is capable of catalyzing substantial acetylation of nucleosomal histone H4 on lysines 5, 8, and 16. In this respect, the NSL HAT complex resembles the NuA4 HAT complex, which also specifically acetylates multiple lysines in the H4 N-terminal tail (32,33).…”

Crystal Structures of Tubulin Acetyltransferase Reveal a Conserved Catalytic Core and the Plasticity of the Essential N Terminus

“…In the monomeric state in solution and in the absence of substrate, this region of TAT is most likely structurally labile and able to adopt variable conformations. TAT is quite unusual as an acetyltransferase as it has an extremely low basal activity with tubulin (0.4 h Ϫ1 ), and even after ϳ8-fold enhancement by the microtubule lattice, its activity is 50 times less than that of GCN5, the prototypical GNAT superfamily member (30). Its low basal activity with tubulin is similar to that of the histone acetyltransferase Rtt109 (0.1 h Ϫ1 (30)).…”