Revealing the protein propionylation activity of the histone acetyltransferase MOF (males absent on the first)

Abstract

Short-chain acylation of lysine residues recently emerges as a group of reversible posttranslational modifications in mammalian cells. The diversity of acylation further broadens the landscape and complexity of the proteome. Identification of regulatory enzymes and effector proteins for lysine acylation is critical to understand functions of these novel modifications at the molecular level. Here, we report that the MYST family of lysine acetyltransferases (KATs) possesses strong propionyltransferase activity both in vitro and in cellulo. Particularly, the propionyltransferase activity of MOF, MOZ, and HBO1 is as strong as their acetyltransferase activity. Overexpression of MOF in human embryonic kidney 293T cells induced significantly increased propionylation in multiple histone and non-histone proteins, which manifests that the function of MOF goes far beyond its canonical histone H4 lysine-16 acetylation. We also resolved the X-ray co-crystal structure of MOF bound with propionyl coenzyme A, which provides a direct structural basis for the propionyltransferase activity of the MYST KATs. Our data together defines a novel function for the MYST KATs as lysine propionyltransferases and suggests much broader physiological impacts for this family of enzymes.

Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability

“…KAT8 is critical for histone H4K16 propionylation in vivo. In addition to H4K16 acetylation, KAT8 promotes histone propionylation in vitro (36), but it is unclear which lysine residue is propionylated, nor was the physiological relevance investigated. KAT8 is an H4K16 acetyltransferase (6, 7, 9), so we postulated that it is also required for H4K16 propionylation (H4K16pr).…”

“…(Supplemental Figure 10B) to control H4K16 acylation during cerebral development ( Figure 8E). The potential of KAT8 to catalyze H4K16 propionylation is intriguing ( Figure 6, C and D, and Supplemental Figure 7, C and D) (36). The acetyl-CoA concentration is much higher than propionyl-CoA in vivo (56), so propionylation may function as a complementary mechanism under conditions when the propionyl-CoA level is elevated (Supplemental Figure 7E).…”

The many lives of KATs — detectors, integrators and modulators of the cellular environment

“…CBP and p300 are reported to catalyse propionyalation 226 , butyrylation 226 and crotonylation 233,234 , albeit with reduced efficiency compared with acetylation 235 . Similarly, MOF can reportedly catalyse propionyalation 236 and crotonylation 233 , GCN5 can catalyse succinylation 237 , and moZ 236 , HBO1 (reF. 236 ) and PCAF 238 can catalyse propionylation.…”

“…Similarly, MOF can reportedly catalyse propionyalation 236 and crotonylation 233 , GCN5 can catalyse succinylation 237 , and moZ 236 , HBO1 (reF. 236 ) and PCAF 238 can catalyse propionylation. Recent structural studies of GCN5 have shown that the succinyl-CoA molecule binds to the same catalytic pocket as acetyl-CoA but buries deeper into the hydrophobic binding pocket 237 .…”

The non‐specific lethal ( NSL ) complex at the crossroads of transcriptional control and cellular homeostasis

“…This encourages investigation of MOF partner proteins and MOF targets outside of chromatin. Moreover, MOF has been implicated in catalyzing other –acyl chains such as crotonylation and propionylation . However, the precise contribution of MOF and its NSL complex members to non‐acetyl acylations needs further investigation.…”