Local and distal changes in dynamics are caused by an L205R Cushing's syndrome mutant in PRKACA

• 成果类型: Article
• 署名作者: Kalle, Anagha; Wu, Jian; Tawfeeq, Caesar; Kornev, Alexandr P.; Veglia, Gianluigi; Maillard, Rodrigo; Taylor, Susan S.; Jonniya, Nisha Amarnath
• 署名单位: Johns Hopkins University; University of California System; University of California San Diego; University of California System; University of California San Diego; University of Minnesota System; University of Minnesota Twin Cities; University of Minnesota System; University of Minnesota Twin Cities; Georgetown University; Georgetown University; National Institute of Technology (NIT System); National Institute of Technology Andhra Pradesh
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12900
• DOI: 10.1073/pnas.2502898122
• 发表日期: 2025-06-17
• 关键词: dependent protein-kinase; molecular-dynamics; catalytic subunit; energy landscapes; crystal-structure; parameters; mechanisms; simulation; mutations; FRAMEWORK

摘要

Cushing's syndrome (CS) is an abnormal condition characterized by elevated cortisol levels, often resulting from genetic alterations in the PRKACA gene, which encodes the catalytic subunit of cAMP-dependent protein kinase A (PKA-C). The most common CS mutation, L205R, lies at the P + 1 loop. Understanding how this mutation alters the internal allosteric network within PKA-C and changes nucleotide and substrate cooperativity is a major goal. Using molecular dynamics (MD) simulations and protein residue networks based on local spatial pattern (LSP) method, we compare crystal structures ofwild-type PKA-C and L205R. Our findings indicate that L205R not only locally disrupts the P + 1 hydrophobic pocket, leading to the displacement of the P + 1-residue and altered substrate specificity, but also has long-range effects in the linker connecting the A helix to beta strand 1. The MD simulations and LSP analyses also reveal critical changes at the phosphoryl transfer site. Some of these changes are captured in the L205R crystal structure while others are not. With this strategy, we also show how the dynamics of local and distal allosteric networks are differentially influenced by backbone and side-chain dynamics.