A methylated lysine is a switch point for conformational communication in the chaperone Hsp90.

Nature Communications
Alexandra RehnJ Buchner

Abstract

Methylation of a conserved lysine in C-terminal domain of the molecular chaperone Hsp90 was shown previously to affect its in vivo function. However, the underlying mechanism remained elusive. Through a combined experimental and computational approach, this study shows that this site is very sensitive to sidechain modifications and crucial for Hsp90 activity in vitro and in vivo. Our results demonstrate that this particular lysine serves as a switch point for the regulation of Hsp90 functions by influencing its conformational cycle, ATPase activity, co-chaperone regulation, and client activation of yeast and human Hsp90. Incorporation of the methylated lysine via genetic code expansion specifically shows that upon modification, the conformational cycle of Hsp90 is altered. Molecular dynamics simulations including the methylated lysine suggest specific conformational changes that are propagated through Hsp90. Thus, methylation of the C-terminal lysine allows a precise allosteric tuning of Hsp90 activity via long distances.

References

Jan 1, 1991·Methods in Enzymology·R S Sikorski, J D Boeke
Oct 1, 1995·European Journal of Biochemistry·T NemotoK Yokoyama
Jul 1, 1995·Molecular and Cellular Biology·D F Nathan, S Lindquist
Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Mar 21, 1997·The Journal of Biological Chemistry·W SullivanD Toft
Dec 16, 1997·Proceedings of the National Academy of Sciences of the United States of America·D F NathanS Lindquist
May 15, 1998·Nature·G García-CardeñaW C Sessa
Jul 7, 2001·The Journal of Biological Chemistry·K RichterJ Buchner
Apr 4, 2002·Journal of the National Cancer Institute·Xiaodan YuDavid S Schrump
Sep 27, 2002·The Journal of Biological Chemistry·William P SullivanDavid O Toft
Dec 31, 2002·Molecular Cell·Barry PanaretouChrisostomos Prodromou
Sep 15, 2004·Journal of Molecular Biology·Klaus RichterJohannes Buchner
Jun 7, 2005·Proceedings of the National Academy of Sciences of the United States of America·Antonio Martínez-RuizSantiago Lamas
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Apr 21, 2006·Nature·Maruf M U AliLaurence H Pearl
Sep 20, 2006·Molecular and Cellular Biology·Patricija HawleWolfgang M J Obermann
Jan 16, 2007·Molecular Cell·Bradley T ScrogginsLen Neckers
Oct 24, 2007·Molecular and Cellular Biology·Oyetunji A ToogunBrian C Freeman
Feb 23, 2008·The Biochemical Journal·Laurence H PearlPaul Workman
Apr 11, 2008·The Journal of Biological Chemistry·Klaus RichterJohannes Buchner
Apr 30, 2008·The Journal of Biological Chemistry·Sebastian Karl WandingerJohannes Buchner
Feb 24, 2009·Nature Structural & Molecular Biology·Martin HesslingJohannes Buchner
Feb 24, 2009·Nature Structural & Molecular Biology·Moritz MicklerThorsten Hugel
Aug 22, 2009·EMBO Reports·Marco RetzlaffJohannes Buchner
Nov 17, 2009·Journal of Molecular Biology·Lenka Kundrat, Lynne Regan
Nov 26, 2009·Proceedings of the National Academy of Sciences of the United States of America·Elana S EhrlichXiao-Fang Yu
Feb 18, 2010·Molecular Cell·Marco RetzlaffJohannes Buchner
Apr 8, 2010·Cell Stress & Chaperones·David MittelmanJohn H Wilson
Jun 10, 2010·Nature Reviews. Molecular Cell Biology·Mikko TaipaleSusan Lindquist

❮ Previous
Next ❯

Citations

Jun 13, 2020·The Journal of Biological Chemistry·Sarah J BackeMehdi Mollapour
Jul 16, 2021·British Journal of Pharmacology·Xiyue ZhangLiping Xie

❮ Previous
Next ❯

Methods Mentioned

BETA
X-ray
fluorescence resonance
FRET
acetylation
Fluorescence

Software Mentioned

MODELLER
CHARMM27
NAMD
Visual
Origin
SEDVIEW

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.