Advanced

Global structural motions from the strain of a single hydrogen bond

Danielsson, Jens; Abdelhady, Wael Awad LU ; Kadhirvel, Saraboji LU ; Kurnik, Martin; Lang, Lisa; Leinartaite, Lina; Marklund, Stefan L.; Logan, Derek LU and Oliveberg, Mikael (2013) In Proceedings of the National Academy of Sciences 110(10). p.3829-3834
Abstract
The origin and biological role of dynamic motions of folded enzymes is not yet fully understood. In this study, we examine the molecular determinants for the dynamic motions within the beta-barrel of superoxide dismutase 1 (SOD1), which previously were implicated in allosteric regulation of protein maturation and also pathological misfolding in the neurodegenerative disease amyotrophic lateral sclerosis. Relaxation-dispersion NMR, hydrogen/deuterium exchange, and crystallographic data show that the dynamic motions are induced by the buried H43 side chain, which connects the backbones of the Cu ligand H120 and T39 by a hydrogen-bond linkage through the hydrophobic core. The functional role of this highly conserved H120-H43-T39 linkage is to... (More)
The origin and biological role of dynamic motions of folded enzymes is not yet fully understood. In this study, we examine the molecular determinants for the dynamic motions within the beta-barrel of superoxide dismutase 1 (SOD1), which previously were implicated in allosteric regulation of protein maturation and also pathological misfolding in the neurodegenerative disease amyotrophic lateral sclerosis. Relaxation-dispersion NMR, hydrogen/deuterium exchange, and crystallographic data show that the dynamic motions are induced by the buried H43 side chain, which connects the backbones of the Cu ligand H120 and T39 by a hydrogen-bond linkage through the hydrophobic core. The functional role of this highly conserved H120-H43-T39 linkage is to strain H120 into the correct geometry for Cu binding. Upon elimination of the strain by mutation H43F, the apo protein relaxes through hydrogen-bond swapping into a more stable structure and the dynamic motions freeze out completely. At the same time, the holo protein becomes energetically penalized because the twisting back of H120 into Cu-bound geometry leads to burial of an unmatched backbone carbonyl group. The question then is whether this coupling between metal binding and global structural motions in the SOD1 molecule is an adverse side effect of evolving viable Cu coordination or plays a key role in allosteric regulation of biological function, or both? (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
allostery, local unfolding, metal binding, protein aggregation, structural frustration
in
Proceedings of the National Academy of Sciences
volume
110
issue
10
pages
3829 - 3834
publisher
National Acad Sciences
external identifiers
  • wos:000316377400042
  • scopus:84874588889
ISSN
1091-6490
DOI
10.1073/pnas.1217306110
language
English
LU publication?
yes
id
5d736f91-dbfb-4a0f-b65a-9274dfc098e6 (old id 3765117)
date added to LUP
2013-05-20 09:44:07
date last changed
2019-07-30 01:10:57
@article{5d736f91-dbfb-4a0f-b65a-9274dfc098e6,
  abstract     = {The origin and biological role of dynamic motions of folded enzymes is not yet fully understood. In this study, we examine the molecular determinants for the dynamic motions within the beta-barrel of superoxide dismutase 1 (SOD1), which previously were implicated in allosteric regulation of protein maturation and also pathological misfolding in the neurodegenerative disease amyotrophic lateral sclerosis. Relaxation-dispersion NMR, hydrogen/deuterium exchange, and crystallographic data show that the dynamic motions are induced by the buried H43 side chain, which connects the backbones of the Cu ligand H120 and T39 by a hydrogen-bond linkage through the hydrophobic core. The functional role of this highly conserved H120-H43-T39 linkage is to strain H120 into the correct geometry for Cu binding. Upon elimination of the strain by mutation H43F, the apo protein relaxes through hydrogen-bond swapping into a more stable structure and the dynamic motions freeze out completely. At the same time, the holo protein becomes energetically penalized because the twisting back of H120 into Cu-bound geometry leads to burial of an unmatched backbone carbonyl group. The question then is whether this coupling between metal binding and global structural motions in the SOD1 molecule is an adverse side effect of evolving viable Cu coordination or plays a key role in allosteric regulation of biological function, or both?},
  author       = {Danielsson, Jens and Abdelhady, Wael Awad and Kadhirvel, Saraboji and Kurnik, Martin and Lang, Lisa and Leinartaite, Lina and Marklund, Stefan L. and Logan, Derek and Oliveberg, Mikael},
  issn         = {1091-6490},
  keyword      = {allostery,local unfolding,metal binding,protein aggregation,structural frustration},
  language     = {eng},
  number       = {10},
  pages        = {3829--3834},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Global structural motions from the strain of a single hydrogen bond},
  url          = {http://dx.doi.org/10.1073/pnas.1217306110},
  volume       = {110},
  year         = {2013},
}