Molecular dynamics simulations to investigate the domain swapping mechanism of human cystatin C

Yuan Min Lin, Hsuan Liang Liu, Jian Hua Zhao, Chi Hung Huang, Hsu Wei Fang, Yih Ho, Wen Yih Chen

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Human cystatin C (HCC), one of the amyloidgenic proteins, has been proved to form a dimeric structure via a domain swapping process and then cause amyloid deposits in the brains of patients suffering from Alzheimer's disease. HCC monomer consists of a core with a five-stranded antiparallel β-sheet (β region) wrapped around a central helix. The connectivity of these secondary structures is: (N)-β1-α-β2-L1-β3-AS-β4-L2- β5-(C). In this study, various molecular dynamics simulations were conducted to investigate the conformational changes of the monomeric HCC at different temperatures (300 and 500 K) and pH levels (2, 4, and 7) to gain insight into the domain swapping mechanism. The results show that high temperature (500 K) and low pH (pH 2) will trigger the domain swapping process of HCC. We further proposed that the domain swapping mechanism of HCC follows four steps: (1) the α-helix moves away from the β region; (2) the contacts between β2 and β3-AS disappear; (3) the β2-L1-β3 hairpin unfolds following the so-called "zip-up" mechanism; and finally (4) the HCC dimer is formed. Our study shows that high temperature can accelerate the unfolding of HCC and the departure of the α-helix from the β-region, especially at low pH value. This is attributed to the fact that that low pH results in the protonation of the side chains of Asp, Glu, and His residues, which further disrupts the following four salt-bridge interactions stabilizing the α-β interface of the native structure: Asp15-Arg53 (β1-β2), Glu21/20-Lys54 (helix-β2), Asp40-Arg70 (helix-AS), and His43-Asp81 (β2-AS).

Original languageEnglish
Pages (from-to)577-584
Number of pages8
JournalBiotechnology Progress
Volume23
Issue number3
DOIs
Publication statusPublished - May 2007

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Cystatin C
cystatins
molecular dynamics
Molecular Dynamics Simulation
Temperature
temperature
Amyloid Plaques
amyloid
Alzheimer disease
Viperidae
Alzheimer Disease
Salts
salts
brain
Brain

ASJC Scopus subject areas

  • Food Science
  • Biotechnology
  • Microbiology

Cite this

Molecular dynamics simulations to investigate the domain swapping mechanism of human cystatin C. / Lin, Yuan Min; Liu, Hsuan Liang; Zhao, Jian Hua; Huang, Chi Hung; Fang, Hsu Wei; Ho, Yih; Chen, Wen Yih.

In: Biotechnology Progress, Vol. 23, No. 3, 05.2007, p. 577-584.

Research output: Contribution to journalArticle

Lin, Yuan Min ; Liu, Hsuan Liang ; Zhao, Jian Hua ; Huang, Chi Hung ; Fang, Hsu Wei ; Ho, Yih ; Chen, Wen Yih. / Molecular dynamics simulations to investigate the domain swapping mechanism of human cystatin C. In: Biotechnology Progress. 2007 ; Vol. 23, No. 3. pp. 577-584.
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abstract = "Human cystatin C (HCC), one of the amyloidgenic proteins, has been proved to form a dimeric structure via a domain swapping process and then cause amyloid deposits in the brains of patients suffering from Alzheimer's disease. HCC monomer consists of a core with a five-stranded antiparallel β-sheet (β region) wrapped around a central helix. The connectivity of these secondary structures is: (N)-β1-α-β2-L1-β3-AS-β4-L2- β5-(C). In this study, various molecular dynamics simulations were conducted to investigate the conformational changes of the monomeric HCC at different temperatures (300 and 500 K) and pH levels (2, 4, and 7) to gain insight into the domain swapping mechanism. The results show that high temperature (500 K) and low pH (pH 2) will trigger the domain swapping process of HCC. We further proposed that the domain swapping mechanism of HCC follows four steps: (1) the α-helix moves away from the β region; (2) the contacts between β2 and β3-AS disappear; (3) the β2-L1-β3 hairpin unfolds following the so-called {"}zip-up{"} mechanism; and finally (4) the HCC dimer is formed. Our study shows that high temperature can accelerate the unfolding of HCC and the departure of the α-helix from the β-region, especially at low pH value. This is attributed to the fact that that low pH results in the protonation of the side chains of Asp, Glu, and His residues, which further disrupts the following four salt-bridge interactions stabilizing the α-β interface of the native structure: Asp15-Arg53 (β1-β2), Glu21/20-Lys54 (helix-β2), Asp40-Arg70 (helix-AS), and His43-Asp81 (β2-AS).",
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