Next Article in Journal
The Arabidopsis Calcium-Dependent Protein Kinases (CDPKs) and Their Roles in Plant Growth Regulation and Abiotic Stress Responses
Next Article in Special Issue
Conformational Dynamics of Herpesviral NEC Proteins in Different Oligomerization States
Previous Article in Journal
Farnesoid X Receptor Activation Enhances Transforming Growth Factor β-Induced Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma Cells
Previous Article in Special Issue
Nonnative Energetic Frustrations in Protein Folding at Residual Level: A Simulation Study of Homologous Immunoglobulin-like β-Sandwich Proteins
Open AccessArticle

Anti-Correlation between the Dynamics of the Active Site Loop and C-Terminal Tail in Relation to the Homodimer Asymmetry of the Mouse Erythroid 5-Aminolevulinate Synthase

1
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
2
Department of Chemistry, College of Arts and Sciences, University of South Florida, Tampa, FL 33612, USA
3
USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
4
Institute for Biological Instrumentation of the Russian Academy of Sciences, Pushchino, Moscow 142290, Russia
*
Author to whom correspondence should be addressed.
Current address: Boston Children’s Hospital/Harvard Medical School, Boston, MA 02115, USA.
Int. J. Mol. Sci. 2018, 19(7), 1899; https://doi.org/10.3390/ijms19071899
Received: 9 April 2018 / Revised: 21 June 2018 / Accepted: 22 June 2018 / Published: 28 June 2018
(This article belongs to the Special Issue Protein Structural Dynamics)
Biosynthesis of heme represents a complex process that involves multiple stages controlled by different enzymes. The first of these proteins is a pyridoxal 5′-phosphate (PLP)-dependent homodimeric enzyme, 5-aminolevulinate synthase (ALAS), that catalyzes the rate-limiting step in heme biosynthesis, the condensation of glycine with succinyl-CoA. Genetic mutations in human erythroid-specific ALAS (ALAS2) are associated with two inherited blood disorders, X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP). XLSA is caused by diminished ALAS2 activity leading to decreased ALA and heme syntheses and ultimately ineffective erythropoiesis, whereas XLPP results from “gain-of-function” ALAS2 mutations and consequent overproduction of protoporphyrin IX and increase in Zn2+-protoporphyrin levels. All XLPP-linked mutations affect the intrinsically disordered C-terminal tail of ALAS2. Our earlier molecular dynamics (MD) simulation-based analysis showed that the activity of ALAS2 could be regulated by the conformational flexibility of the active site loop whose structural features and dynamics could be changed due to mutations. We also revealed that the dynamic behavior of the two protomers of the ALAS2 dimer differed. However, how the structural dynamics of ALAS2 active site loop and C-terminal tail dynamics are related to each other and contribute to the homodimer asymmetry remained unanswered questions. In this study, we used bioinformatics and computational biology tools to evaluate the role(s) of the C-terminal tail dynamics in the structure and conformational dynamics of the murine ALAS2 homodimer active site loop. To assess the structural correlation between these two regions, we analyzed their structural displacements and determined their degree of correlation. Here, we report that the dynamics of ALAS2 active site loop is anti-correlated with the dynamics of the C-terminal tail and that this anti-correlation can represent a molecular basis for the functional and dynamic asymmetry of the ALAS2 homodimer. View Full-Text
Keywords: ALAS; homodimer asymmetry; molecular dynamics; intrinsically disordered region; anti-correlated dynamics ALAS; homodimer asymmetry; molecular dynamics; intrinsically disordered region; anti-correlated dynamics
Show Figures

Figure 1

MDPI and ACS Style

Na, I.; Catena, D.; Kong, M.J.; Ferreira, G.C.; Uversky, V.N. Anti-Correlation between the Dynamics of the Active Site Loop and C-Terminal Tail in Relation to the Homodimer Asymmetry of the Mouse Erythroid 5-Aminolevulinate Synthase. Int. J. Mol. Sci. 2018, 19, 1899.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop