title: Acetylation of a conserved lysine residue in the ATP binding pocket of p38 augments its kinase activity during hypertrophy of cardiomyocytes.
abstract: Like phosphorylation, acetylation of lysine residues within a protein is considered a biologically relevant modification that controls the activity of target proteins. During stress of cells, massive protein acetylation takes place. Here, we show that p38 mitogen-activated protein kinase (MAPK), which controls many biological functions during stress, is reversibly acetylated by PCAF/p300 and HDAC3. We identified two acetylated lysine residues, K152 and K53, located in the substrate binding domain and in the ATP-binding pocket of p38, respectively. Acetylation of lysine 53 enhanced the activity of p38 by increasing its affinity for ATP binding. The enhanced acetylation and activation of p38 were found to be in parallel with reduced intracellular ATP levels in cardiomyocytes under stress, as well as in vivo models of cardiac hypertrophy. Thus, our data show, for the first time, that p38 activity is critically regulated by, in addition to phosphorylation, reversible acetylation of a lysine residue, which is conserved in other kinases, implying the possibility of a similar mechanism regulating their activity.
authors: Department of Surgery, University of Chicago Medical Center, Chicago, Illinois 60637, USA.
authors: Vinodkumar B
authors: VB
authors: Pillai
authors: Nagalingam R
authors: NR
authors: Sundaresan
authors: Sadhana A
authors: SA
authors: Samant
authors: Don
authors: D
authors: Wolfgeher
authors: Chinmay M
authors: CM
authors: Trivedi
authors: Mahesh P
authors: MP
authors: Gupta
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D057809:HEK293 Cells; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy; D013058:Mass Spectrometry; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D011499:Protein Processing, Post-Translational; D051381:Rats; D013312:Stress, Physiological; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor; D000099186:Histone Deacetylase 3
chemical_list: D000123:Acetyltransferases; D000255:Adenosine Triphosphate; D006655:Histone Deacetylases; D050880:p300-CBP Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000099224:p300-CBP-Associated Factor; D000099186:Histone Deacetylase 3