Name
Title | ||
|---|---|---|
Simulations of Pathogenic E1 alpha Variants: Allostery and Impact on Pyruvate Dehydrogenase Complex-E1 Structure and Function |
Abstract | ||
|---|---|---|
Pyruvate dehydrogenase complex (PDC) deficiency is a major cause of primary lactic acidemia resulting in high morbidity and mortality, with limited therapeutic options. The E1 component of the mitochondrial multi-enzyme PDC (PDC-E1) is a symmetric dimer of heterodimers (alpha beta/alpha & PRIME;beta & PRIME;) encoded by the PDHA1 and PDHB genes, with two symmetric active sites each consisting of highly conserved phosphorylation loops A and B. PDHA1 mutations are responsible for 82-88% of cases. Greater than 85% of E1 alpha residues with disease-causing missense mutations (DMMs) are solvent-inaccessible, with & SIM;30% among those involved in subunit-subunit interface contact (SSIC). We performed molecular dynamics simulations of wild-type (WT) PDC-E1 and E1 variants with E1 alpha DMMs at R349 and W185 (residues involved in SSIC), to investigate their impact on human PDC-E1 structure. We evaluated the change in E1 structure and dynamics and examined their implications on E1 function with the specific DMMs. We found that the dynamics of phosphorylation Loop A, which is crucial for E1 biological activity, changes with DMMs that are at least about 15 A away. Because communication is essential for PDC-E1 activity (with alternating active sites), we also investigated the possible communication network within WT PDC-E1 via centrality analysis. We observed that DMMs altered/ disrupted the communication network of PDC-E1. Collectively, these results indicate allosteric effect in PDC-E1, with implications for the development of novel small-molecule therapeutics for specific recurrent E1 alpha DMMs such as replacements of R349 responsible for similar to 10% of PDC deficiency due to E1 alpha DMMs. |
Year | DOI | Venue |
|---|---|---|
2022 | 10.1021/acs.jcim.2c00630 | JOURNAL OF CHEMICAL INFORMATION AND MODELING |
DocType | Volume | Issue |
Journal | 62 | 14 |
ISSN | Citations | PageRank |
1549-9596 | 0 | 0.34 |
References | Authors | |
0 | 3 | |
Name | Order | Citations | PageRank |
|---|---|---|---|
| Hatice Gokcan | 1 | 0 | 0.34 |
| Jirair K Bedoyan | 2 | 0 | 0.34 |
| Olexandr Isayev | 3 | 1 | 0.70 |