TY - JOUR

T1 - Histone chaperone exploits intrinsic disorder to switch acetylation specificity

AU - Danilenko, Nataliya

AU - Lercher, Lukas

AU - Kirkpatrick, John

AU - Gabel, Frank

AU - Codutti, Luca

AU - Carlomagno, Teresa

N1 - Funding Information: We thank ILL (D22 BAG system, BAG8-34, BAG8-36) and JCNS-MLZ (KWS-1 beam-time) for the SANS experiments; Dr. A. Martel (ILL, Grenoble) and Dr. A. Feoktystov (JCNS-MLZ, Garching) for help with the instrumental setup and SANS data collection. L. L. acknowledges the receipt of an EMBO Long-term Fellowship (ALTF 1474-2014, Marie Curie Actions, LTFCOFUND2013, GA-2103-609409).

PY - 2019/8/6

Y1 - 2019/8/6

N2 - Histones, the principal protein components of chromatin, contain long disordered sequences, which are extensively post-translationally modified. Although histone chaperones are known to control both the activity and specificity of histone-modifying enzymes, the mechanisms promoting modification of highly disordered substrates, such as lysine-acetylation within the N-terminal tail of histone H3, are not understood. Here, to understand how histone chaperones Asf1 and Vps75 together promote H3 K9-acetylation, we establish the solution structural model of the acetyltransferase Rtt109 in complex with Asf1 and Vps75 and the histone dimer H3:H4. We show that Vps75 promotes K9-acetylation by engaging the H3 N-terminal tail in fuzzy electrostatic interactions with its disordered C-terminal domain, thereby confining the H3 tail to a wide central cavity faced by the Rtt109 active site. These fuzzy interactions between disordered domains achieve localization of lysine residues in the H3 tail to the catalytic site with minimal loss of entropy, and may represent a common mechanism of enzymatic reactions involving highly disordered substrates.

AB - Histones, the principal protein components of chromatin, contain long disordered sequences, which are extensively post-translationally modified. Although histone chaperones are known to control both the activity and specificity of histone-modifying enzymes, the mechanisms promoting modification of highly disordered substrates, such as lysine-acetylation within the N-terminal tail of histone H3, are not understood. Here, to understand how histone chaperones Asf1 and Vps75 together promote H3 K9-acetylation, we establish the solution structural model of the acetyltransferase Rtt109 in complex with Asf1 and Vps75 and the histone dimer H3:H4. We show that Vps75 promotes K9-acetylation by engaging the H3 N-terminal tail in fuzzy electrostatic interactions with its disordered C-terminal domain, thereby confining the H3 tail to a wide central cavity faced by the Rtt109 active site. These fuzzy interactions between disordered domains achieve localization of lysine residues in the H3 tail to the catalytic site with minimal loss of entropy, and may represent a common mechanism of enzymatic reactions involving highly disordered substrates.

UR - http://www.scopus.com/inward/record.url?scp=85070260736&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-11410-7

DO - 10.1038/s41467-019-11410-7

M3 - Article

C2 - 31387991

AN - SCOPUS:85070260736

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 3435

ER -