Structural and Thermodynamic Characteristics of Amyloidogenic Intermediates of β-2-Microglobulin

Overview

Journal Sci Rep

Specialty Science

Date 2015 Sep 9

PMID 26348154

Citations 6

Authors

Song-Ho Chong

Jooyeon Hong

Sulgi Lim

Sunhee Cho

Jinkeong Lee

Sihyun Ham

Affiliations

Soon will be listed here.

Abstract

β-2-microglobulin (β2m) self-aggregates to form amyloid fibril in renal patients taking long-term dialysis treatment. Despite the extensive structural and mutation studies carried out so far, the molecular details on the factors that dictate amyloidogenic potential of β2m remain elusive. Here we report molecular dynamics simulations followed by the solvation thermodynamic analyses on the wild-type β2m and D76N, D59P, and W60C mutants at the native (N) and so-called aggregation-prone intermediate (IT) states, which are distinguished by the native cis- and non-native trans-Pro32 backbone conformations. Three major structural and thermodynamic characteristics of the IT-state relative to the N-state in β2m protein are detected that contribute to the increased amyloidogenic potential: (i) the disruption of the edge D-strand, (ii) the increased solvent-exposed hydrophobic interface, and (iii) the increased solvation free energy (less affinity toward solvent water). Mutation effects on these three factors are shown to exhibit a good correlation with the experimentally observed distinct amyloidogenic propensity of the D76N (+), D59P (+), and W60C (-) mutants (+/- for enhanced/decreased). Our analyses thus identify the structural and thermodynamic characteristics of the amyloidogenic intermediates, which will serve to uncover molecular mechanisms and driving forces in β2m amyloid fibril formation.

Citing Articles

Investigation of D76N β-Microglobulin Using Protein Footprinting and Structural Mass Spectrometry.

Cornwell O, Ault J, Bond N, Radford S, Ashcroft A J Am Soc Mass Spectrom. 2021; 32(7):1583-1592.

PMID: 33586970 PMC: 9282677. DOI: 10.1021/jasms.0c00438.

Enhanced accessibility and hydrophobicity of amyloidogenic intermediates of the β2-microglobulin D76N mutant revealed by high-pressure experiments.

Sakurai K, Tomiyama R J Biol Chem. 2021; 296:100333.

PMID: 33508321 PMC: 7950326. DOI: 10.1016/j.jbc.2021.100333.

The Early Phase of β2-Microglobulin Aggregation: Perspectives From Molecular Simulations.

Loureiro R, Faisca P Front Mol Biosci. 2020; 7:578433.

PMID: 33134317 PMC: 7550760. DOI: 10.3389/fmolb.2020.578433.

The role of the I-state in D76N β-microglobulin amyloid assembly: A crucial intermediate or an innocuous bystander?.

Smith H, Guthertz N, Cawood E, Maya-Martinez R, Breeze A, Radford S J Biol Chem. 2020; 295(35):12474-12484.

PMID: 32661194 PMC: 7458819. DOI: 10.1074/jbc.RA120.014901.

Analysis of molecular dynamics simulations of 10-residue peptide, chignolin, using statistical mechanics: Relaxation mode analysis and three-dimensional reference interaction site model theory.

Maruyama Y, Takano H, Mitsutake A Biophys Physicobiol. 2020; 16:407-429.

PMID: 31984194 PMC: 6975981. DOI: 10.2142/biophysico.16.0_407.

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