Residues flanking the ARK^me3T/S motif allow binding of diverse targets to the HP1 chromodomain: Insights from molecular dynamics simulations

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14310%2F21%3A00118823" target="_blank" >RIV/00216224:14310/21:00118823 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68081707:_____/21:00542005

Výsledek na webu

<a href="https://doi.org/10.1016/j.bbagen.2020.129771" target="_blank" >https://doi.org/10.1016/j.bbagen.2020.129771</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bbagen.2020.129771" target="_blank" >10.1016/j.bbagen.2020.129771</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Residues flanking the ARK^me3T/S motif allow binding of diverse targets to the HP1 chromodomain: Insights from molecular dynamics simulations

Popis výsledku v původním jazyce

Background: The chromodomain (CD) of HP1 proteins is an established H3K9(me3) reader that also binds H1, EHMT2 and H3K23 lysine-methylated targets. Structural experiments have provided atomistic pictures of its recognition of the conserved ARK(me3)S/T motif, but structural dynamics' contribution to the recognition may have been masked by ensemble averaging. Methods: We acquired similar to 350 mu s of explicit solvent molecular dynamics (MD) simulations of the CD domain interacting with several peptides using the latest AMBER force fields. Results: The simulations reproduced the experimentally observed static binding patterns well but also revealed visible structural dynamics at the interfaces. While the buried K-0(me3) and A(-2) target residues are tightly bound, several flanking sidechains sample diverse sites on the CD surface. Different amino acid positions of the targets can substitute for each other by forming mutually replaceable interactions with CD, thereby explaining the lack of strict requirement for cationic H3 target residues at the -3 position. The Q(-4) residue of H3 targets further stabilizes the binding. The recognition pattern of the H3K23 ATK(me3)A motif, for which no structure is available, is predicted. Conclusions: The CD reads a longer target segment than previously thought, ranging from positions -7 to +3. The CD anionic clamp can be neutralized not only by the -3 and -1 residues, but also by -7, -6, -5 and +3 residues. General Significance: Structural dynamics, not immediately apparent from the structural data, contribute to molecular recognition between the HP1 CD domain and its targets. Mutual replaceability of target residues increases target sequence flexibility.

Název v anglickém jazyce

Residues flanking the ARK^me3T/S motif allow binding of diverse targets to the HP1 chromodomain: Insights from molecular dynamics simulations

Popis výsledku anglicky

Background: The chromodomain (CD) of HP1 proteins is an established H3K9(me3) reader that also binds H1, EHMT2 and H3K23 lysine-methylated targets. Structural experiments have provided atomistic pictures of its recognition of the conserved ARK(me3)S/T motif, but structural dynamics' contribution to the recognition may have been masked by ensemble averaging. Methods: We acquired similar to 350 mu s of explicit solvent molecular dynamics (MD) simulations of the CD domain interacting with several peptides using the latest AMBER force fields. Results: The simulations reproduced the experimentally observed static binding patterns well but also revealed visible structural dynamics at the interfaces. While the buried K-0(me3) and A(-2) target residues are tightly bound, several flanking sidechains sample diverse sites on the CD surface. Different amino acid positions of the targets can substitute for each other by forming mutually replaceable interactions with CD, thereby explaining the lack of strict requirement for cationic H3 target residues at the -3 position. The Q(-4) residue of H3 targets further stabilizes the binding. The recognition pattern of the H3K23 ATK(me3)A motif, for which no structure is available, is predicted. Conclusions: The CD reads a longer target segment than previously thought, ranging from positions -7 to +3. The CD anionic clamp can be neutralized not only by the -3 and -1 residues, but also by -7, -6, -5 and +3 residues. General Significance: Structural dynamics, not immediately apparent from the structural data, contribute to molecular recognition between the HP1 CD domain and its targets. Mutual replaceability of target residues increases target sequence flexibility.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/GA18-07384S" target="_blank" >GA18-07384S: Od konformace po biologické funkce proteinu HP1</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Biochimica et Biophysica Acta - General Subjects

ISSN

0304-4165

e-ISSN

1872-8006

Svazek periodika

1865

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

12

Strana od-do

1-12

Kód UT WoS článku

000594131800032

EID výsledku v databázi Scopus

2-s2.0-85094907445