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Binding Mechanism and Dynamic Conformational Change of C Subunit

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Binding Mechanism and Dynamic Conformational Change of C Subunit Binding mechanism and dynamic conformational PNAS PLUS change of C subunit of PKA with different pathways Wen-Ting Chua,1, Xiakun Chub,1, and Jin Wanga,c,2 aState Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; bInstituto Madrileno˜ de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Campus Universitario de Cantoblanco, 28049 Madrid, Spain; and cDepartment of Chemistry and Physics, State University of New York at Stony Brook, Stony Brook, NY 11794 Edited by Jose´ N. Onuchic, Rice University, Houston, TX, and approved July 31, 2017 (received for review February 22, 2017) The catalytic subunit of PKA (PKAc) exhibits three major confor- (12). However, because of the highly dynamic characteristics, the mational states (open, intermediate, and closed) during the bio- structure of PKAc is elusive. The first crystallographic structure catalysis process. Both ATP and substrate/inhibitor can effectively of PKAc was successfully solved by Knighton et al. (7) via cocrys- induce the conformational changes of PKAc from open to closed talizing a high-affinity protein binding inhibitor (PKI), a 20-aa states. Aiming to explore the mechanism of this allosteric regu- peptide of heat stable protein, including a high-affinity pseu- lation, we developed a coarse-grained model and analyzed the dosubstarte region and a nuclear export signal (13). The PKAc dynamics of conformational changes of PKAc during binding by dynamics are found to be quenched by the high-affinity binding performing molecular dynamics simulations for apo PKAc, binary interactions from PKI, making the structure of PKAc accessi- PKAc (PKAc with ATP,PKAc with PKI), and ternary PKAc (PKAc with ble (14, 15). Additional experiments revealed that the binding ATP and PKI). Our results suggest a mixed binding mechanism affinity of ATP and PKI will be cooperatively enhanced by each of induced fit and conformational selection, with the induced fit other. The high affinity between PKI and PKAc-ATP will block dominant. The ligands can drive the movements of Gly-rich loop substrate binding, supporting the evidence of PKI serving as an as well as some regions distal to the active site in PKAc and sta- inhibitor for PKAc (16, 17). bilize them at complex state. In addition, there are two paral- Structural investigations revealed that PKAc populates at lel pathways (pathway with PKAc-ATP as an intermediate and three main conformations, which can be classified into open, pathway PKAc-PKI as an intermediate) during the transition from closed, and intermediate states based on the conformation of open to closed states. By molecular dynamics simulations and rate active site cleft (12, 14, 15, 18). The apo PKAc dominates at open constant analyses, we find that the pathway through PKAc-ATP state (dynamically uncommitted to catalysis), with minor popu- intermediate is the main binding route from open to closed state lations at other states, while the presence of ligand (nucleotide because of the fact that the bound PKI will hamper ATP from suc- or substrate/inhibitor) alters this conformational equilibrium to cessful binding and significantly increase the barrier for the sec- favor the intermediate or closed states (dynamically committed) ond binding subprocess. These findings will provide fundamental (14, 15). During the binding process, the conformational changes insights of the mechanisms of PKAc conformational change upon of PKAc mostly occur in the Gly-rich loop, between the cat- binding. alytic and peptide-positioning loops, and in the C-terminal por- tion (18). In practice, people have pointed out some critical dis- conformational change j PKA j binding j energy landscape j tances as the criteria to classify the different states of PKAc, such α molecular dynamics as the distance between carbon atom (CA) of Ser53 and CA of Gly186 (measuring the opening and closing of the Gly-rich loop), the distance between NE2 of His87 and phosphate oxygen ransferring of ATP terminal phosphates to target protein of phospho-Thr197 (measuring the position of C helix relative to substrates, referred to as protein phosphorylation, by cAMP- the large lobe), and the distance between O of Glu170 and OH T BIOPHYSICS AND dependent PKA is one of the most important biomolecular pro- cesses involved in many cellular activities, including metabolism, Significance COMPUTATIONAL BIOLOGY growth, memory, and cell differentiation (1, 2). PKA is one of the largest families in eukaryotes, widely spread in many species PKA is one of the largest kinase families in eukaryotes. The and many places. Thanks to the recent developments in struc- conformational change of catalytic subunit of PKA (PKAc) is tural biology, an arresting amount of structures of PKA, which linked to the substrate recognition and catalytic activity. We mainly belongs to humans, mice, and pigs, has been well-solved quantified the free energy landscapes of PKAc dynamics and PHYSICS and deposited into Protein Data Bank (PDB) (3–11). It greatly uncovered the binding mechanism of two different ligands, deepens our understanding on PKA’s biological regulation pro- ATP and PKI to PKAc, by using the weighted coarse-grained cess through a conventional “structure–function” regime. model and molecular dynamics simulations. Our results sug- The inactive PKA is a holoenzyme composed of two regula- gest mixed binding mechanism of induced fit and conforma- tory (R) subunits, which provide the binding sites for cAMP, tional selection and favor the pathway with PKAc-ATP as an and two catalytic (C) subunits, which include the critical active intermediate (ATP binding first). Also, our studies indicate the and binding sites for ATP and substrates/inhibitors (12). The critical residues at different stages of binding during the con- catalytic subunit of PKA (PKAc) is highly conserved both in formational change process from open to closed states. sequence and structure. In general, the PKAcs have 350 residues, with two phosphorylation sites at Thr197 and Ser338 (denoted Author contributions: W.-T.C., X.C., and J.W. designed research; W.-T.C. and X.C. per- as pThr197 and pSer338). For 3D structure, PKAc comprises a formed research; W.-T.C., X.C., and J.W. analyzed data; and W.-T.C., X.C., and J.W. wrote kidney-shaped core (residue 40–300), which consists of a small the paper. N-terminal β-sheet dominated lobe (ATP binding site; residue The authors declare no conflict of interest. 40–119), a large helical-rich lobe (substrate/inhibitor binding This article is a PNAS Direct Submission. site; residue 128–300), and the linker between them (residue 1W.-T.C. and X.C. contributed equally to this work. 120–127) (12) (Fig. 1). The intrinsic dynamics of PKAc, which 2To whom correspondence should be addressed. Email: [email protected]. is mostly contributed by opening and closing the active site cleft, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. is found to be prevalent and critical to its regulation function 1073/pnas.1702599114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1702599114 PNAS j Published online August 30, 2017 j E7959–E7968 Downloaded by guest on October 1, 2021 26 apo AB 24 22 20 Glycine-rich loop 18 Tyr330 Ser53 α Mg-positioning C 16 ATP Gly186 loop Glu127 His87 14 Catalytic loop Glu170 Asp166 pThr197 12 PKI 10 8 6 8 10 12 14 16 18 20 22 open-PNAS closed-PNAS intermediate-PNAS CDE 26 26 26 binary-ATP binary-PKI ternary 24 24 24 22 22 22 20 20 20 18 18 18 16 16 16 14 14 14 12 12 12 10 10 10 8 8 8 6 8 10 12 14 16 18 20 22 6 8 10 12 14 16 18 20 22 6 8 10 12 14 16 18 20 22 0 1 2 3 4 5 (kT) Fig. 1. (A) PKAc structure and (B–E) the free energy landscapes of PKAc dynamics along critical distances between Ser53 and Gly186 (x axis) and Ser53 and Asp166 (y axis) in different systems [(B) apo PKAc (apo), (C) PKAc-ATP (binary-ATP), (D) PKAc-PKI (binary-PKI), and (E) PKAc-ATP-PKI (ternary)]. PDB ID code 1ATP is illustrated as the PKAc-ATP-PKI ternary complex. Ligand ATP is shown as spheres (between small and large lobes of PKAc), and ligand PKI is shown as purple cartoons. For PKAc, small lobe (40–119), large lobe (128–300), and linker (120–127) are shown as red, light orange, and blue cartoons, respectively. Glycine-rich loop (46–57; colored in yellow) belongs to small lobe, and catalytic loop (116–171) and Mg-positioning loop (both colored in green) belong to large lobe. Three main distances of six residue pairs (Ser53-Gly186, His87-Thr197, and Glu170-Tyr330), which are used to distinguish different states of PKAc, are labeled in A. The classification of open, closed, and intermediate states is referred to the data in the work of Masterson et al. (15). of Tyr330 (measuring the distance of the C-terminal tail to the Results and Discussion active site) (12, 19). Dynamic Conformational Equilibrium in apo PKAc. The structure- Based on the abundant static structures (bound states) of based model (SBM) (29–31), which generally has only one basin PKAc, additional insights are moving to understand the rela- at the bottom of the energy landscape representing the native tionship between conformation and function by uncovering the structure, has successfully described the protein folding and conformational dynamics of PKAc during binding. Recently, binding processes. However, such a simplified model may fail NMR-based investigations by Masterson et al. (14, 15) por- to describe the particular case where protein has multiple con- trayed an energy landscape of PKAc binding with substrate formations, each corresponding to a specific function within the phospholamban (PLN) and inhibitor PKI.
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